CA3133004A1

CA3133004A1 - Btk inhibitor ring derivative, preparation method therefor and pharmaceutical application thereof

Info

Publication number: CA3133004A1
Application number: CA3133004A
Authority: CA
Inventors: Chen Zhang; Yuting LIAO; Jianmin Wang; Guozhi ZHU; Fei Ye; Pingming TANG; Xiaogang Chen; Zhenggang HUANG; Shoutao WU; Yao Li; Pangke YAN
Original assignee: Sichuan Haisco Pharmaceutical Co Ltd
Current assignee: Haisco Pharmaceuticals Pte Ltd
Priority date: 2019-05-31
Filing date: 2020-05-29
Publication date: 2020-12-03
Also published as: SG11202110085TA; US11542266B1; CN113544130B; BR112021024131A2; TWI762939B; EP3978496A4; TW202110825A; KR20220016049A; WO2020239103A1; MX2021012756A; AU2020281410A1; CN118027041A; IL287332A; JP2022534650A; EP3978496A1; CN113544130A; EP3978496B1

Abstract

A BTK inhibitor ring derivative, a preparation method therefor and a pharmaceutical application thereof. The BTK inhibitor ring derivative is a compound represented by a general formula (I) or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or co-crystal thereof, and the BTK inhibitor ring derivative is used to treat BTK-related diseases such as tumors or autoimmune system diseases.

Description

Description BTK INHIBITOR RING DERIVATIVE, PREPARATION METHOD THEREFOR
AND PHARMACEUTICAL APPLICATION THEREOF
Technical Field The present invention relates to a compound represented by general formula (I) or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, and intermediates thereof and preparation methods io therefor, as well as the use thereof in BTK-related diseases such as tumors or autoimmune system diseases.
Background Art Bruton's tyrosine kinasc (BTK), a member of the Tec family of non-receptor protein tyrosine kinases, is a key regulator in the B cell antigen receptor (BCR) signaling pathway, and is distributed in the lymphatic system, hematopoietic and blood system. BTK mutations may activate downstream signaling pathways in tumor cell proliferation, differentiation, and angiogenesis, etc., which may lead to X-linked agammaglobulinemia, non-Hodgkin's lymphoma (NHL) and many B-cell malignancies, including chronic lymphocytic leukaemia (CLL), mantle cell lymphoma, and diffuse large B-cell lymphoma. As mainly expressed in B cells and myeloid cells, BTK is a target with relatively high targeting ability and safety.
PROTAC (proteolysis targeting chimera) molecules are a class of dual function compounds which are capable of binding to both targeted proteins and E3 ubiquitin li gases. This class of compounds can induce recognition of targeted proteins by proteasomes in a cell to cause the degradation of the targeted protein, which can effectively reduce the contents of the targeted proteins in the cell. By introducing a ligand capable of binding to various targeted proteins into the PROTAC
molecules, it is possible to apply the PROTAC technology to the treatment of various diseases, and this technology has attracted extensive attention in recent years.
Date Recue/Date Received 2021-09-09

2 Summary of the Invention The present invention develops a BTK inhibitor with a novel structure, good efficacy, high bioavailability and higher safety, for use in the treatment of BTK-related diseases such as tumors or autoimmune system diseases.
The present invention develops a PROTAC compound of BTK inhibitors and E3 ubiquitin ligases which has a novel structure, good efficacy, high bioavailability, higher safety, and can inhibit or degrade BTKs, for use in the treatment of BTK-related diseases such as tumors or autoimmune system diseases.
The present invention relates to a compound represented by general formula (I) or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein B-L-K (I);
L is selected from -Akl -Cyl-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;
Akl, Ala, Ak3, Ak4 and Ak5 are each independently selected from CH,, 0 or a bond;
Cyl, Cy2, Cy3 and Cy4 are each independently selected from 3- to 12-membered heterocyclic ring, 3-to 12-membered cycloalkyl, 6-to 10-membered aryl or a bond, wherein the heterocyclic ring, cycloalkyl or aryl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH2, oxo (=0), C14 alkyl or C1,4 alkoxy, and the heterocyclic ring contains I to 4 heteroatoms selected from 0, S or N;
Cyl, Cy2, Cy3 and Cy4 cannot all be a bond;
when Akl , Ak2, Ak3, Ak4 or Ak5 is 0, they cannot be directly connected to B;
when Akl, Ak2, Ak3, Ak4 or Ak5 is not a bond, they cannot be directly connected to one another;
when 3 of Cyl, Cy2, Cy3 and Cy4 are a bond, at least one of Akl, Ak2, Ak3, Ak4, and Ak5 is selected from CH2 and is connected to B;
when 4 or more of Akl, Cyl, Ak2, Cy2, Ak3, Cy3, Ak4, Cy4 and Ak5 are not a bond, at least one of Cyl, Cy2, Cy3 and Cy4 is not piperidine, piperazine, pyrimidine or pyridine;
B is selected from Bl-Wl-B2-B3-B4-;
Date Recue/Date Received 2021-09-09

3 B1 is selected from 6-membered heteroaryl ring or phenyl, wherein the heteroaryl ring or phenyl is optionally further substituted with 0 to 4 Rbi, and the heteroaryl ring contains I to 4 heteroatoms selected from 0, S or N;
W1 is selected from -0-, -S-, -NH-, -NHCO- or -CONH-;
B2 is selected from 6-membered heteroaryl ring or phenyl, wherein the heteroaryl ring or phenyl is optionally further substituted with 0 to 4 le2, and the heteroaryl ring contains I to 4 heteroatoms selected from 0, S or N;
B3 is selected from 8- to 10-membered fused heterocyclic ring, wherein the fused heterocyclic ring is optionally further substituted with 0 to 4 le3, and the fused heterocyclic ring contains 1 to 4 heteroatoms selected from 0, S or N;
B4 is selected from 5- to 6-membered saturated heterocyclic ring, wherein the saturated heterocyclic ring is optionally further substituted with 0 to 4 R", and the saturated heterocyclic ring contains 1 to 2 heteroatoms selected from 0, S or N;
Rbi, Rb2, Rb3 or R" is each independently selected from H, F, Cl, Br, 1, OH, N1-12, CN, CONH,, C1_4 alkyl or C1_4 alkoxy, and the alkyl and alkoxy are optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, N11.2, CN, CONH2, C1-4 alkyl or C1_4 alkoxy;
(Rk3),õ
Fe8 r-N
K is selected from o Rk2 is selected from CH2, C-0, S-0, or S02;
r.k3 c. or R" is each independently selected from H, F, Cl, Br, 1, OH, N112, CN, COOH, C14 alkyl or C1-4 alkoxy;
Rk5 is selected from C=0 or pl or p2 is each independently selected from 0, 1, 2, 3 or 4.
It should be understood that Akl, Ak2, Ak3, Ak4 and Ak5, as well as Cyl, Cy2, Cy3 and Cy4, as well as B2, B3 and B4 of the present invention are subunits when they are each independently substituents.
Some embodiments of the present invention relate to a compound represented by general formula (I) or a stereoisomer, a solvate, a prodrug, a metabolite, a Date Recue/Date Received 2021-09-09

4 pharmaceutically acceptable salt or a co-crystal thereof, wherein L is selected from -Akl -Cyl-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;
Akl, Ak2, Ak3, Ak4 and Ak5 are each independently selected from CH2, 0 or a bond; Cy l, Cy2, Cy3 and Cy4 are each independently selected from 3-membered heterocyclic ring, 4-membered heterocyclic ring, 5-membered heterocyclic ring, me mbered heterocyclic ring, 7-membered heterocyclic ring, 8-membered heterocyclic ring, 9-membered heterocyclic ring, 10-membered heterocyclic ring, 11-membered heterocyclic ring, 12-membered heterocyclic ring, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 7-membered cycloalkyl, 8-membered cycloalkyl, 9-membered cycloalkyl, 10-membered cycloalkyl, 11-membered cycloalkyl, 12-membered cycloalkyl, 6- to 10-membered aryl or a bond, preferably a bond, 4-membered mono-heterocyclic ring,

5-membered mono-heterocyclic ring, 6-membered mono-heterocyclic ring, 7-membered mono-heterocyclic ring, 5-membered fused heterocyclic ring, 6-membered fused heterocyclic ring, 7-membered fused heterocyclic ring, 8-membered fused heterocyclic ring, 9-membered fused heterocyclic ring, 10-membered fused heterocyclic ring, 6-membered spiro-heterocyclic ring, 7-membered spiro-heterocyclic ring, 8-membered spiro-heterocyclic ring, 9-membered spiro-heterocyclic ring, 10-membered spiro-heterocyclic ring, 11-membered spiro-heterocyclic ring, I 2-membered spiro-heterocyclic ring, 7-membered bridged-heterocyclic ring, 8-membered bridged-heterocyclic ring, 9-membered bridged-heterocyclic ring, 10-membered bridged-heterocyclic ring, 4-membered monocycloalkyl, 5-membered monocycloalkyl, 6-membered monocycloalkyl, 7-membered monocycloalkyl, 5-membered fused cycloalkyl, 6-membered fused cycloalkyl, 7-membered fused cycloalkyl, 8-membered fused cycloalkyl, 9-membered fused cycloalkyl, 10-membered fused cycloalkyl, 6-membered Spiro cycloalkyl, 7-membered Spiro cycloalkyl, 8-membered Spiro cycloalkyl, 9-membered spiro cycloalkyl, 10-membered spiro cycloalkyl, 11-membered spiro cycloalkyl, membered spiro cycloalkyl, 7-membered bridged cycloalkyl, 8-membered bridged cycloalkyl, 9-membered bridged cycloalkyl, 10-membered bridged cycloalkyl or 6-10-membered aryl, wherein the aryl, cycloalkyl, mono-heterocyclic ring, fused Date Recue/Date Received 2021-09-09 heterocyclic ring, spiro-heterocyclic ring or bridged-heterocyclic ring is optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br, I, OH, NH2, 02W, C1-4 alkyl or C1-4 alkoxy, and the mono-heterocyclic ring, fused heterocyclic ring, spiro-heterocyclic ring or bridged-heterocyclic ring contains 1, 2, 5 3 or 4 heteroatoms selected from 0, S or N;
Cyl, Cy2, Cy3 and Cy4 cannot all be a bond;
when Akl, Ak2, Ak3, Ak4 or Ak5 is 0, they cannot be directly connected to B;
when Akl, Ak2, Ak3, Ak4 or Ak5 is not a bond, they cannot be directly connected to one another;
when 3 of Cyl, Cy2, Cy3 and Cy4 are a bond, at least one of Akl, Ak2, Ak3, Ak4, and Ak5 is selected from Cl-I2 and is connected to B;
when 4 or more of Akl, Cyl, Ak2, Cy2, Ak3, Cy3, Ak4, Cy4 and Ak5 are not a bond, at least one of Cyl, Cy2, Cy3 and Cy4 is not piperidine, piperazine, pyrirnidine or pyridine;
B is selected from BI-WI -B2-B3-B4-;
B I is selected from 6-membered heteroaryl ring or phenyl, preferably phenyl or pyridyl, wherein the heteroaryl ring, phenyl or pyridyl is optionally further substituted with 0, 1, 2, 3 or 4 Rbl, and the heteroaryl ring contains 1, 2, 3 or 4 heteroatoms selected from 0, S or N;
WI is selected from -0-, -NHCO- or -CON H-;
B2 is selected from 6-membered heteroaryl ring or phenyl, preferably phenyl or pyridyl, wherein the heteroaryl ring, phenyl or pyridyl is optionally further substituted with 0, 1, 2, 3 or 4 It1'2, and the heteroaryl ring contains 1, 2, 3 or 4 heteroatoms selected from 0, S or N;
B3 is selected from 8-membered fused heterocyclic ring, 9-membered fused heterocyclic ring or 10-membered fused heterocyclic ring, preferably substituted or unsubstituted i midazopyri mid Me, pyrazol opyri mid ine, imidazopyrazine, pyrazolopyrazine, imidazotetrahydropyrimidine, or pyrazolotetrahydropyrimidine, when substituted, wherein the fused heterocyclic ring, imidazopyrimidine, pyrazolopyrimidine, imidazopyrazine, pyrazolopyrazine, imidazotetrahydropyrimidine, or pyrazolotetrahydropyrimidine is optionally further Date Recue/Date Received 2021-09-09

6 substituted with 0, 1, 2, 3 or 4 R.1'3, and the fused heterocyclic ring contains 1, 2, 3 or 4 heteroatoms selected from 0, S or N;
B4 is selected from 5-membered saturated heterocyclic ring or 6-membered saturated heterocyclic ring, preferably substituted or unsubstituted azacyclopentyl, piperidine or piperazine, wherein the heterocyclic ring, azacyclopentyl, piperidine or piperazine is optionally further substituted with 0, 1, 2, 3 or 4 R", and the saturated heterocyclic ring contains 1 to 2 heteroatoms selected from 0, S or N;
(Rk1),, (Rk3)p2 .,Rk2 i Nk5 N, K is selected from o (Rki)pi 0 (Rci)pl N
NH NH
or K can be selected from o 0 0 0 or , H

o H
NH \ ,., or K can be selected from o 0 , F 0 H

11--------\N¨c, 0 NH 1 ___,, ...:õ.1..,_ 0 0 or N" -= , õ¨

N----c. ---0 0 1101---e-5-/¨NH
or K can be selected from 0 o 0 o , , o o o o 0 C) NH NH le t4 Ft NH

F F 0N 0 NI yo F A.

NH F 15 ' _-1\-.1 N ¨0 1+-. ¨0 N

Date Recue/Date Received 2021-09-09

7 -"\ 0 ;',' N----cNH "zi. N----NH O N---NH 0 0 0 -- 0 0 --H
ONO H
0 ".--' "--7" 0 N 0 H H
N
,i...
-r- , ""\ = ,),.....
o 0 0 N_tNH

\
or K can be selected from 0 0 , o , o o A NH F NH
,,..--,..õ____, ;Vt`--H
0 -,-- -----N (-) N (:) N-----"-----) or N
, Rk2 is selected from CH2, C-0, S=0, or S02;
R , Rk3 or Rk4 is each independently selected from H, F, Cl, Br, I, OH, NH2, CN, COOH, C1-4 alkyl or C1-4 alkoxy;
¨
Rks is selected from C-0 or AN.-)-------;
pl or p2 is each independently selected from 0, 1, 2, 3 or 4.
According to some embodiments of the present invention, wherein L is selected from -Akl-Cyl-Ak2-Cy2-A1c3-Cy3-Ak4-Cy4-Ak5-;
Akl, Alc2, Ak3, Ak4 and Ak5 are each independently selected from CH2, 0 or a bond;
Cy 1 , Cy2, Cy3 and Cy4 are each independently selected from 3- to 12-membered heterocyclic ring, 3- to 12-membered cycloalkyl, 6-to 10-membered aryl or a bond, wherein the heterocyclic ring, cycloalkyl or aryl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br or I, and the heterocyclic ring contains 1 to 4 heteroatoms selected from 0, S or N.
According to some embodiments of the present invention, wherein Ak2, Ak3 Date Recue/Date Received 2021-09-09 and Ak4 are bonds; Akl and Ak5 are each independently selected from CH2, 0 or a bond.
Some embodiments of the present invention relate to a compound represented by general formula (1.) or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein L is selected from -Akl-Cyl -Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;
Akl, Ak2, Ak3, Ak4 and Ak5 are each independently selected from CH,, 0 or a bond;
Cyl , Cy2, Cy3 and Cy4 are each independently selected from a substituted or unsubstituted bond, phenyl, naphthyl, eyelobutyl, cyclopentyl, cyclohexyl, cycl butyl- fused -eye lobutyl, cyclobutyl-fused-cyclopentyl, cyclobutyl- fused -cycl ohexyl, cyclopentyl-fused-cyclopentyl, cyclopentyl-fused-cyclohexyl, cyclohexyl-fused-cyc lohexyl, cyclopropyl-fused-cyclobutyl, cyclopropyl-fused-cyclopentyl, cyclopropyl-fused-cyclohexyl, cyclobutyl-spiro-cyclobutyl, cyclobutyl-spiro-cyclopentyl, cyclobutyl-spiro-cyclohexyl, cyclopentyl-spiro-cyclopentyl, cyclopentyl-spiro-cyclohexyl, cyclohexyl-spiro-cyclohexyl, cyclopropyl-spiro-cycl butyl, cyclopropyl-spiro-cyclopentyl, cyclopropyl-spiro-cyclohexyl, azetidinyl, azacyclopentyl, piperidyl, morpholinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, cyclopropyl-fused-azetidinyl, cyclopropyl-fused-azacyclopentyl, cyclopropyl-fused-azacyc lohexyl, cyc lopropy 1- fused -p iperidyl, cyclobutyl-fused-azetidinyl, cyclobutyl-fused-azacyclopentyl, cyclobutyl-fused-azacyclohexyl, cyclobutyl-fused-piperidyl, cyclopentyl-fused-azetidinyl, cyclopentyl-fused-azacyelopentyl, cyclopentyl-fused-azacyclohexyl, cyclopentyl-fused-piperidyl, eye lohexyl-fused-azetidinyl, cyclohexyl-fused-azacyclopentyl, cyclohcxyl-fused-azacyclohcxyl, cyclohexyl-fused-piperidyl, azetidinyl-fused-azetidinyl, azetidi nyl- fused-azacyc lopenty 1, azetidinyl-fused-azacyc lohexyl, azetidinyl-fused-piperidyl, azacyclopentyl-fused-azetidinyl, azacyclopentyl-fused-azacyclopentyl, azacyclopentyl-fused-azacyclohexyl, azacyclopentyl-fused-piperidyl, azacyclohexyl-fused-azetidinyl, azacyclohexyl-fused-azacyclopentyl, azacyclohexyl-fused-azacyclohexyl, azacyclohexyl-fused-piperidyl, eye lobutyl-Date Recue/Date Received 2021-09-09 spiro-azetidinyl, cyclobutyl-spiro-azacyclopentyl, eye lobutyl-spiro-azacyclohexyl, cyclopentyl-spiro-azetidinyl, eye lope ntyl- spiro-azacyc lopentyl, cyclopentyl-spiro-azacyclohexyl, cyclohexy 1 -spiro-azetidinyl, cyclohexyl-spiro-azacyclopentyl, cyclohexyl-spiro-azacyclohexyl, azetidinyl-spiro-azetidinyl, azetidinyl-spiro-s azacyclopentyl, azetidinyl-spiro-azacyclohexyl, azacyc lopentyl-spiro-azetid ny I, azacyclopentyl-sp iro-azacyc lopenty I, azacyclopentyl-spiro-azacyclohexyl, azacyclohexyl-spiro-azetidinyl, azacyclohexyl-spiro-azacyclopentyl, azacyclohexyl-spiro-azacyclohexyl, cyclobutyl-spiro-piperidyl, cyclopentyl-spiro-piperidyl, cyclohexyl-spiro-piperidyl, azetidinyl-spiro-piperidyl, azacyc I opentyl-spiro-1,N
piperidyl, azacycl hex yl-spiro-piperidyl, 0 , preferably a substituted or unsubstituted bond, phenyl, naphthyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, piperidyl, morpholinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, azetidinyl-fused-azetidinyl, azetidinyl-fused-azacyclopentyl, azetidinyl-fused-azacyclohexyl, azetidinyl-fused-piperidyl, azacyclopentyl-fused-azetidinyl, azacyclopentyl-fused-azacyclopentyl, azacyclopentyl-fused-azacyclohcxyl, azacyclopentyl-fused-piperidyl, cyclohexyl-sp iro-azetidi ny 1, cyclobuty I -spiro-azacyc lohexyl, cyc lopenty l-fused-azacyc I openty I, azacyc lohexy 1- fused-azetid inyl, azacyclohexyl-fused-azacyc I opentyl, azetid inyl-spiro-azetidinyl, azetidinyl-spiro-azacyclopentyl, azetidinyl-spiro-azacyclohexyl, azacyclopentyl-spiro-azetidinyl, azacyclopentyl-sp iro-azacyclopenty I, azacyclopentyl-spiro-azacyclohexyl, azacyclohexyl-spiro-azetidinyl, azacyclohexyl-sp iro-azac ye lopcnty I, azacyc lohcxyl -spiro-azacyclohexyl, azetidinyl-spiro-piperidyl, ¨.0-1-azacyclopentyl-spiro-piperidyl, or ;
which, when substituted, are optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br, 1, OH, NH2, oxo, C1-4 alkyl or C1-4 alkoxy, preferably substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br, 1, OH, NH2, oxo, methyl, ethyl, isopropyl, Date Recue/Date Received 2021-09-09 methoxy, ethoxy or isopropoxy;
Cyl, Cy2, Cy3 and Cy4 cannot all be a bond;
when Akl, Ak2, Ak3, Ak4 or Ak5 is 0, they cannot be directly connected to B;
when Akl, Ak2, Ak3, Ak4 or Ak5 is not a bond, they cannot be directly 5 connected to one another;
when 3 of Cyl, Cy2, Cy3 and Cy4 are a bond, at least one of Akl, Ak2, Ak3, Ak4, and Ala is selected from CH2 and is connected to B;
when 4 or more of Akl, Cyl, Ak2, Cy2, Ak3, Cy3, Ak4, Cy4 and Ak5 are not a bond, at least one of Cyl, Cy2, Cy3 and Cy4 is not piperidyl, piperazinyl, 10 pyrimidinyl or pyridyl;
(Rb3),õ7 N r----7-,-' \ I q /I-4,N
(Rb1) (R) N
L---__/¨ \ (Rbl ), (R112)õ2 cA.N
(Rb,4)ne i-i----, it-r- --N- \--_-1_P+

,.,..---"---0,--:---'tz/
B is selected from (R b4),, , ,` or Ni.-------<11-N, ,,, / N
0 H2N N k H2N---_c_..).N
,N,..õ ) __ L,.._,..('':\r ¨NH ''''' -' N 'c---Ini2 N¨CINI-NN
CV(R''2).-lo (R.,), 410 0 , preferably, ao , , NH2 N--- \
HN FN / \>

N
N
Cr" .
, N ------NN (Rb4)n4 --- .
N¨( M-N _________________________________________________________________ or B can be selected from H NI
N
Kt-,---r 1.- - -- - - = - - - ____________________________________ N (R").-.4 ")._-(Rb.4)ne, X or ' Date Recue/Date Received 2021-09-09 N----\\

N
/ 1\ (W4)/112 ,) 1-..\----0.-r-=-N-- NH
N, - N /
\NI- 0 \NI'N,...___"..I
or B can be selected from N / 6 40 t 0 , , N.,,,, N.-,-\
H2N -1 H2N N\
N
FI2N---,N
r.õ2 1/4---/ 2., O
, , , p 114,_ 0 H2N --\ 1\1,-, \ / N F H2N -UN H2N--ON _ t--0- _-N, ...., 60-0- <11-1N...c.1 60-G- N,,,a,, c5 \N
N , IN
......
III 0 C.NI
I

N.",N HN

0 _EN) N
H2N ' N C\ NV N; ) HN j NH
N
, o o hi2N-p N
0 =\1 'N ---0 .\1115' /-1-31,41 rik or , Rbi, Rb2, _t,c ¨ b3 or KM is each independently selected from H, F, Cl, Br, 1, OH, NH2, CN, CONH2, C1-4 alkyl or C1_4 alkoxy, preferably selected from H, F, Cl, Br, I, OH, NH.), CN, CONH2, methyl or methoxy; the methyl, methoxy, alkyl and alkoxy are to optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br, 1, OH, NH2, CN, CONH2, C1_4 alkyl or C1_4 alkoxy, preferably substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br or I;
nl, n2, n3, n4, n5, n6, n7, n8, n9, n10, n11, and n12 are each independently Date Recue/Date Received 2021-09-09 selected from 0, 1, 2, 3 or 4;
(Rk3),2 (Rki)p, (R2)õ2 0 Rk,.2N _.5.:__ )=0 N.---- N
K is selected from o 0 'Rk4 or 0 'Rk4 , preferably H

t (<KNI 0 -------1---- NI----7_ 0 0 0 0 0 r -------N-- -.'" =
; ;
(Rki)po 0 (Rki)pi or K can be selected from o 0 o 0 or , H
(Rid)pill0 _5 ri---1----------N

14....,....õ. ___ .\.c NH \ z or K can be selected from 0 0 , F 0 /
H

0 y- --.,------1¨N---c 0 ....-, ,..
NH V-Li....õ.<5....õ ,..,j_..
0 o or N-- ---- ;

I o N¨c-NH
or K can be selected from o o NH NH NH
N NH Z¨

N 0 y --''z.
F F F

' 7 ...Z.-NH 00 00 N ______ F
Nii- NH F .v...A .ZNI*1 N 0=--- µ
0 . 0 a ,___. ___ c, -NH
0 ; 0 ; 0 ; 1¨ 00 ;
H

"i" N"--." ______________ N 0 ¨c-NH
N- -\C) N

; ; ;
Date Recue/Date Received 2021-09-09 0 `-.G" _ 0 0X:T0 ) N 0 or --- -N

NH
or K can be selected from o o NH
NH
tO N =fD

0 Cky- N

NH
0 0 0 or Rk2 is selected from CH) or C=0;
Rkl, Rk3 or Rk4 is each independently selected from H, F, Cl, Br,!, OH, NH2, CN, COOH, CIA alkyl or C]..4 alkoxy, preferably H, F, Cl, Br, I, OH or NH?;
pl or p2 is each independently selected from 0, 1 or 2.
Some embodiments of the present invention relate to a compound represented by general formula (I) or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein L is selected from -Akl -Cyl-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;
Ak 1, Ak2, Ak3, Ak4 and Ak5 are each independently selected from CH2, 0 or a bond;
Cyl, Cy2, Cy3 and Cy4 are each independently selected from a substituted or unsubstituted bond, phenyl, naphthyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutyl-fused-cyclobutyl, cyclobutyl-fused-cyclopentyl, cyclobutyl-fused-cyclohexyl, cyclopentyl-fused-cyclopentyl, cyclopentyl-fused-cyclohexyl, cycl ohexyl-fused-cyc lohexy I, cyclopropyl -fused -cyc lobutyl, eye lopropyl-fused-cycl opentyl, cyclopropyl-fused-cyclohexyl, cyclobutyl-spiro-cyclobutyl, cyclobutyl-spiro-cyclopentyl, cyclobutyl-spiro-cyclohexyl, cyclopentyl-spiro-cyclopentyl, cycl op entyl-sp iro-cycl ohexyl, cyclohcxyl-spiro-cyclohexyl, eye lopropy 1-spiro-cycl butyl, cyclopropyl-spiro-cyclopentyl, cyclopropyl-spiro-cyclohexyl, azeti din yl, Date Recue/Date Received 2021-09-09 60-60-1=ZOZPanpoaapcuen5aele0 liculppazu-posnj-iicumpozu 'j 0Z1.fl 0ZlU
`pculzu.licd Ircuputpicci `iicuFzuppicd licppicd liCiozeILD `pCiozumup `pCjozuk{c1 `pCloit/Cd laufzund!d liCullogcliow 1/Cppod!d `pcomodoioX3uzu pCuIppozu `iXxotioloi.C3 liCluodoloiCa `I/C_Incioio/C.3 liCtpticluu liCuotid `puoq polni!Iscittsun poirupsqns u Xiquaojani 5 5 ,0 1Xpliod!d-oi!ds-pcxoqopicauz13 '1Xppodid N
-04S-11c11u0dOpX1Ezu `pcppod!d-wIds-pCuwpozu `1/Cmod!d-0.10s-pCxotioloXa Xppci!ci-allds-p(itiadopi6 1Xppacild-oilds-pC1ngopi6 `IXtiolnkynzu-ands -1Xxogoi3Xouzu li(luodoioXonzu-oi!ds-IXxogoioXanzu 'EXuiptlozu-ands-pcxotiolorCauzu licxotiopicauzu-o4s-ircluodo13/c0EZU
IX1110d013X3BZU-alldSlicitiOdOpicaBZE OZ
licumgozu-o.gds-IXTuodolaXauzu `IXxotiopiCauzu-oi!cls-pCulppozu `pCitiodoioX3EZB
-oi!ds-pCuwpozu 1./Culp-pzu-o.r0s-pCu!pp0z1 p{xogoloiCouzu-oi!ds-pCxotiotoiCa `IXTuodopiCauzu-ol!ds-I/CxatiolDiCO
liCulpliozu-ca!ds-iXxagopiCa `pCxogolo/Ouzu -omds-pcittoclopica `p(modopAprzu-omdslicludoloica lictiwpzu-omds-tAluodopica 1/4xatiopicauzu-at!ds-IXincioioX3 licluodoloicouzu-w!dis-IX1nciopica licumipzu-onds si Iklagopico pCppod!d-postmiXxogopXouzu cycyagoloXouzu-postu-IXxogoioXouzu Xluoclop/Ouzu-posnj-ii(xotiopiCauzu lAumpozu-posrinAxogoloAnzu 1Xppod!cl-postijapCmcloi3X3uzu 1Xxoqopicouzu-posnj-IXTuodoloX3uzu IX1u3doloXouzu-postmiXluadoloXouzu `1Xu!ppozu-pasnilicluadoioXp1z13 `-pcppod!d-postij-ticumpozu `pcxoqopicouzu-posnj-liculppozu 1A1113d010/caUZB OT
-posnj-iXu!piwze `pcuylpzu-posnj-pcuypozu `1XpInd!d-posnj-pcxotiojaic3 licxaqopicauzu-pasnj-pCxagopiCo liCluadolo/CDuzu-pasrinXxagop/Co IiCumpozu -posni-pCxoqopiCo lAppocild-posnj-jklU3dOIOAD lAxogoloAnzu-posnj-iAluodopAo IXiumdopXouzu-rosnj-EXItradopXo '1X1Emwzr-psnj-lkiipcio1aico µpcppad!d -postu-pcmcioloX3 `1Xxoqopicouze-posnj-ticiricioloico 1XmodoloXotze-posnj-pcmcioloXa licumpoze-psn4-ricincioloX3 'Exp!nd!daposnj-pcdoidoloico `1Xxotioroicaezu -psni-i/CdoidopiCD `Ikitiodolo/C3r7-r-pnsnj-pcdaidolo/CD `pCuyp93713-Fr)snj-TXdcudopiC3 pcjozqo liCiozupT liCu!zEiXd `IXtrwItupiCd liCulzuppiCd liCppXd liciozup!ui! `Eiclozaucci IiCionAd `pCuTzund!d `pCulloqdlout liCppoci!ci liCluodolo/Couzu azetidinyl-fused-azacyclopentyl, azetidinyl-fused-azacyclohexyl, azetidinyl-fused-piperidyl, azacyclopentyl-fused-azetidinyl, azacyclopentyl-fused-azacyclopentyl, azacyclopentyl-fused-azacyclohexyl, azacyclopentyl-fused-piperidyl, cyclohexyl-spiro-azetidinyl, cyclobutyl-spiro-azacyclohexyl, cyclopentyl-fused-azacyclopentyl, 5 azacyc I ohexyl- fused-azetid inyl, azacyclohe xyl -fu sed-azacyc I
opentyl azetidinyl-spiro-azetidinyl, azet idi nyl- sp iro-azacyc lopenty I, azetidinyl-spiro-azacyc I ohexyl, azacyclopentyl-spiro-azetidinyl, azacyclopentyl-spiro-azacyclopentyl, azacyclopentyl-spiro-azacyclohexyl, azacyclohexyl-spiro-azetidinyl, azacyclohexyl-spiro-azacyclopentyl, azacyclohexyl-spiro-azacyclohexyl, azetidinyl-spiro-piperidyl, 10 azacyclopentyl-sp iro-p iperi idyl, or ;
which, when substituted, are optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br, I. OH, NH2, oxo, C1_4 alkyl or C1_4 alkoxy, preferably substituted with 0, 1, 2, 3 or 4 substituents selected from H. F, Cl, Br, 1, 01-1, NH2, oxo, methyl, ethyl, isopropyl, meth oxy, ethoxy or isopropoxy;
15 Cyl, Cy2, Cy3 and Cy4 cannot all be a bond;
when Akl, Ak2, Ak3, Ak4 or Ak5 is 0, they cannot be directly connected to B;
when Akl, Ak2, Ak3, Ak4 or Ak5 is not a bond, they cannot be directly connected to one another;
when 3 of Cyl, Cy2, Cy3 and Cy4 are a bond, at least one of Akl , Ak2, Ak3, Ak4, and Ak5 is selected from C112 and is connected to B;
when 4 or more of Akl, Cyl Ak2, Cy2, Ak3, Cy3, Ak4, Cy4 and Ak5 are not a bond, at least one of Cyl, Cy2, Cy3 and Cy4 is not piperidyl, piperazinyl, pyrimidinyl or pyridyl;
b3 N--=-7:!(Fi)n3 I-32N --(-N,--Hc (Rb1),õ1 (Rb2)n2 N N.--( IN+
et) =-""
B is selected from (Rb4),,4 , preferably N
Fi2N I /¨N
or Date Recue/Date Received 2021-09-09 N (Rb4) 4 H2N N\ A, / \ n ,N¨( N

/
---N
--i-or B can be selected from ---=--- "o , N, N"--=NN il2N -1 \ õ N

N.....< N-- 0 = .Nt 0 ' N

.----%11 or B can be selected from ------,---k-o /0 N,--_, H2N -\ N-, \ / N H2N -1 \ N H2N- N--------\
F /
F \ N
0 = -N
(trans) \N-N4--"Th (cis) -N,,, , \ N \ N
F
0 \ N, ,,,i a_,.N"...
, / /

_(¨N) N -.. , N iµjõ,..01 ---0 or N , N -Rb I , Rb2, lc ri b3 or RI' is each independently selected from H. F, Cl, Br, 1, OH, NH1, CN, CONH2, C1-4 alkyl or C1.4 alkoxy, preferably selected from H, F, Cl, Br, 1, OH, N112, CN, CONII2, methyl or methoxy; the methyl, methoxy, alkyl and alkoxy are optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br, I, OH, NH2, CN, CONH2, C1-4 alkyl or C1-4 alkoxy, preferably substituted with 0, 1, 2, 3 or 4 substituents selected from IT, F, Cl, Br or 1;
n 1, n2, n3, and n4 are each independently selected from 0, 1, 2, 3 or 4;
(Rkl)pi (Fe)2 k2 r (1,e1),, Rk2 'N (R")02 Ns K is selected from o o 'Rk4 or N
0 R" , preferably Date Recue/Date Received 2021-09-09 H

¨ _________ N r---''''------ 1-N
0 ---1 : Ni¨c-II 0 N
.-- 1 O0 00 or (Rki)pi 0 --1 K."! NI--_ )=0 NH
or K can be selected from o 0 , 0 0 or H

(Rki)pl U
or K can be selected from 0 o , H
0 (:).--NO
,-- ! N¨c-0 LiL.-1."N"'--"---"--s 0 0 or ------ -N =
t -_--_J 0 JjJ--- N---/NH (-----i<N¨c _ '\C) ------ NH
or K can be selected from 0 o , 0 0 , NH NH
N.\---NH

_\>\---NH
/0 , Z--- 0 F F F

N 0 No- 0 N 0 , , , , 1.1N )¨\( -"-- =0---NH )4- N¨NH 0 'N¨ 0 N4//--NH o , , t H

_-_ 0 0 N 0 T: H

(NJ
N -,se N.-1õ.. N N
--; , Of , Date Recue/Date Received 2021-09-09 NH
NH
or K can be selected from o o _Z¨Nht NH

N N N)-11 0 0 0 0 or Rk2 is selected from C112 or C=0;
Rk Rk3 or R" is each independently selected from H, F, Cl, Br, I, OH, NH2, CN, COOH, CI-4 alkyl or CI-4 alkoxy, preferably H, F, CI, Br, 1, OH or NH2;
pl or p2 is each independently selected from 0, 1 or 2.
Some embodiments of the present invention relate to a compound represented by general formula (I) or a stereoisomer, a solvate, a prodrug, a metabolite, a to pharmaceutically acceptable salt or a co-crystal thereof, wherein L is selected from -Akl -Cy 1 -Ak 2 -Cy2 -Ak3-Cy3-Ak4-Cy4-Ak5-;
Akl, Ak2, Ak3, Ak4 and Ak5 are each independently selected from Ca), 0 or a bond;
Cyl , Cy2, Cy3 and Cy4 are each independently selected from a substituted or is unsubstituted bond, phenyl, naphthyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutyl-fused-cyclobutyl, eye lobutyl- fused- eye lopentyl, eye lobutyl- fused-cyclohexyl, cyclopentyl-fused-cyclopentyl, cyclopentyl-fused-cyclohexyl, cyclohexyl-fused-cyclohcxyl, cyclopropyl-fused-cyclobutyl, eyclopropyl-fused-cyclopentyl, cyclopropyl-fused-cyclohexyl, cyclobutyl-spiro-cyclobutyl, cyclobutyl-20 spiro-cyclopentyl, cyclobutyl-spiro-cyclohexyl, cyclopentyl-spiro-cyclopentyl, cycl op entyl-sp iro-cycl ohexy I, cyclohexyl-spiro-cyclohexyl, cyclopropyl-spiro-cyclobutyl, eyelopropyl-spiro-cyclopentyl, eyelopropyl-spiro-cyclohexyl, azetidinyl, azacyc lopentyl, pip eridyl, morpholinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, 25 cycl opropyl-fused-azeti dinyl, eye lopropyl-fused-azaeye lopentyl, eye lopropyl-fused-Date Recue/Date Received 2021-09-09 60-60-1=ZOZ panpoe apcuari5a ele0 -1XX014013/0 `pcppod!d-posni-Vjuodoiarcouzu Tcxoqopicouzu-posnj-iicluodolarcauzu IkluadopiCarzu-posnnkitiodopiCaezu `liCumgozu-p3snj-pCiu3dopiCouzu liCppacild -posny-pCuwpazu `p(xagopiCouze-posnj-pCuIppzu 1/CluodopXouzu-posnj-pCuIpp.ozu liCLiwpozu-postij-liCuw!lozu `pCioz-eipi licioz1?p.1 `iXuvulicd liciv!ut!..tXd cpcity-eppicci lAppicci `Vioziemi `iigozrmtiq IXiortiAd 1Xuvriod!d 41Xtmoqdloua licppod!d `1XluodoloXouze Iiculppozu licxotioloX3 `pcluodoloX3 IX4riqopico lictpildru lituaqd `puog pop-gpsqnsun JO poinlpscins t Xiquiojoid ,0 ,0 1/Cpp3d!d-ailds-pCx.Nopi(Duzu `1XmiNi!d -.1_2!a::74 -1 --04s-pcitiodoloic3Bzu `pcppoc4d-culds-pculppze 41/cpliod!d-ailds-pcxoqopica oz = Xppo dild-cuIds-pCluodopAo liCppodtd-o5Ids-pCingopico pcxogerpX_ouzu-oi!ds -pCxotippiCouzu liCluodolo/Couzu-oi!ds-pCxotioloiCauzu liCuIppozu-wIds-IXxogoloiCauzu `1XX011013/C3BZE-0.1IdS-1/C1110d013,COEZU
I1(111?(.1010XBzu-oilds-iAluodolo/Ouzu licupwr-agds-iicluadolaXorzr `1Axagoinicorze-aqdslicu!ppzv rclIndOlOrcaVZV
-01!c1S-liculppzu 1Xulppozu-oi!ds-pcumpzu µ1Xxogoloicauzu-onds-pcxoqopX3 Si `I/CluodopiCauze-tiu!ds-j/CxoqopiCo IiCu!pIloze-o.i!ds-TiCxotiopiCa IX-xogoioXOCZB
`I/C1U0d013A3UZU-0.11dS-1A11.10dOIDAD `pCulppozu-ouIds-iAluodoioXa licxNap/Couzu-o4s-p(lnqopX3 IXTuodoioXmzu-w!ds-pqnqopXa `iXtimIlDzB-w!ds -1X1ncloioico Ii(pliadld-pastmlicxagoiaXanzu iXxo go]
aXarze-pastu -1 xagoio Xouzr, licluodo picouzu- posnji xapp/corze `iiculppozu-posimpcxol[010/caUZB OT
licppodird-posnj-pcluodoloicouzu `pcxogoloicorze-posnj-pcluodopicopze licluadopiCD-rzu-pasnj-VwdopiCaeze licumpazu-posnj-IXiuodolaX3zu lAppoctild-posni-pCumpozu `TAxoqopAnzu-posnj-EiCuIppozu Ikluodolo/Couzu -psniii(ulp!ozu Ikumrpz-e-posnj-iXtr!mozu licp!INI!d-posnj-p(xmiolarca = x otio pic Duze-psnj- xo go.' a/co `licluodo [o/c aezr-postmi X xogoloXo I icttypoze aposnj-iXxogoloico `iXpliod!d-posn3-licluodoroX3 `ptxotioroXpuzu-posnj-iXwodopica j-liClupdopko o7u-p3smji iCiumdop /C:1 /Crlid!d -posnnkinciopiCa `1XxotiopiCouzu-posnj-p(mclopiCo IkwodoloiCouzu-posnnkingotoiCa = Xumpazu-posnj- pCmcio oiCo `E/CpIncl!d-postu-TXdoldoioX3 `1Xxogolo/Coun GI

spiro-azetidinyl, cyclobutyl-spiro-azacyclohexyl, cyclopentyl-fused-azacyclopentyl, azacyclohexyl-fused-azetidinyl, azacyclohexyl-fused-azacyclopentyl, azetidinyl-spiro-azetidinyl, azetidinyl-spiro-azacyclopentyl, azetidinyl-spiro-azacyclohexyl, azacyc opentyl-spiro-azetidi nyl, azacyclopentyl-spiro-azacyclopentyl, 5 azacyclopentyl-spiro-azacyclohexyl, azacyclohexyl-spiro-azetidinyl, azacyclohexyl-spiro-azacyclopentyl, azacyclohexyl-spiro-azacyclohexyl, azetidinyl-spiro-piperidyl, N¨i-azacyclopentyl-spiro-piperidyl, or ;
which, when substituted, are optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br, 1, OH, NH2, oxo, C1-4 alkyl or C1-4 alkoxy, preferably substituted with 0, 1, 2, 3 10 or 4 substituents selected from H, F, Cl, Br, I, OH, NH,, oxo, methyl, ethyl, isopropyl, inethoxy, ethoxy or isopropoxy;
Cyl, Cy2, Cy3 and Cy4 cannot all be a bond;
when Akl, Ak2, Ak3, Ak4 or Ak5 is 0, they cannot be directly connected to B;
when Akl, Ak2, Ak3, Ak4 or Ak5 is not a bond, they cannot be directly 15 connected to one another;
when 3 of Cyl, Cy2, Cy3 and Cy4 are a bond, at least one of Akl, Ak2, Ak3, Ak4, and Ak5 is selected from C112 and is connected to B;
when 4 or more of Akl, Cyl, Ak2, Cy2, Ak3, Cy3, Ak4, Cy4 and Ak5 are not a bond, at least one of Cyl, Cy2, Cy3 and Cy4 is not piperidyl, piperazinyl, 20 pyrimidinyl or pyridyl;
(FR.b3)õ, NH2 N

(Rbi )n5 (Rb2V6 R ,N
1,4) B is selected from , preferably HN

r%.1NI
or B can be selected from HN

a = 04N
0 HzN CNV
or B can be selected from or .
Date Recue/Date Received 2021-09-09 Rh% fe2, V or Rm is each independently selected from H, F, Cl, Br, 1, OH, NH2, CN, CONH2, C1_4 alkyl or C1_4 alkoxy, preferably selected from H, F, Cl, Br, 1, OH, NH2, CN, CONH2, methyl Of inethoxy; the methyl, inethoxy, alkyl and alkoxy are optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br, 1, OH, NH2, CN, CONH2, C1-4 alkyl or C1-4 alkoxy, preferably substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, CI, Br or I;
n5, n6, n7, and n8 are each independently selected from 0, 1, 2, 3 or 4;
(Rk3)p2 ov.),,2 Fe'2 C====--------\( N
K is selected from o 0 Rk4 or 0 Fik4 , preferably H

--"=. 0 N 0 --sA .__C\f-,0 -A ; _'" N--c0 --i , _ ,6,- N r- -----.'''''=- --)1"-N
--.7.---%"- NH
0 0 00 or ------- -N- ---- , (Rio)p1 0 (p-T
rli Rki) c---c \-- /-0 A ilK__ --\N_/)7_ 0 NH NH
or K can be selected from 0 0 , o 0 or H

(Rkl)pin k,--""--N
Kr '"'= 7 0 o0 tl or K can be selected from o H

0._ _N., 0 --.7- ---------"4----\r\I 0 N^-' 00 or N =

--\(*-------NH o N

or K can be selected from 0 0 , o 0 , N\---NH -N

---.. 1)4=0 No- 0 /0 F F F
0 0 , o 0 , Date Recue/Date Received 2021-09-09 A A A

, N¨c 0 /IS o 'h---------NN 0 i 0 0 0 0 0 0 0 0 H

e N
N i i ---- 14'--L---or , o o 0 NH
\ --LC
N---7---NH-C} F
or K can be selected from o 0 , o ' o o .._Z _____________________________________ NH F
NH
NI- 0 N 4:1 N.... 0 ' H
0 0 0-õ...N.....,0 -j<N.-\- /0 N¨c 0 N------"------0 0 0 or N .
, , Rk2 is selected from CH? or C=0;
Rid, Rk3 or R" is each independently selected from H, F, Cl, Br, 1, OH, NH,, CN, COOH, C1.4 alkyl or C1,4 alkoxy, preferably H, F, Cl, Br, 1, OH or NH2;
pl or p2 is each independently selected from 0, 1 or 2.
Some embodiments of the present invention relate to a compound represented by general formula (1) or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein L is selected from -Akl-Cyl-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;
Ak 1, Ak2, Ak3, Ak4 and Ak5 are each independently selected from CH2, 0 or a bond;
Cyl, Cy2, Cy3 and Cy4 are each independently selected from a substituted or unsubstituted bond, phenyl, naphthyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutyl-fused-cyclobutyl, cyclobutyl-fused-cyclopentyl, cyclobutyl-fused-Date Recue/Date Received 2021-09-09 60-60-1=ZOZ panpoe apcuari5a ele0 -0.11piSIATTIOdOTOXMZB `pcppod0-04s-pCuTpozu lApIlodId-o.r0s-pCxotiotoXa liCppoci!d-culds-IXIuMoloiCo cpcppocild-oilds-IXmcmoiCo .. `pcxo.qopiCouzu-oi!ds -p(xatiopXouzu Iicluocioloicorze-ol!dslicxoqopicarzy. 1Xulmlozu-ands-iXxogoloXouzu *pcxNoloXouzu-ands-IXiuoclopicouzu `1XluodoioXouze-andsliciuodoloXouze icumpozu-at!ds-ikitiodopkiuzu licv.)qopXnuzu-o.gds-licumpozu lititiodoinkluzu sz -ar!ds-pCtimIlazu IiCumpozu-cuIds-IXuypoze 11CxogoTaXouzu-o4s-IXxatiop1Ca licwodop/Ouzu-oi!ds-VxogopiCo liCulppozu-0.1!ds-iXxoqop/C3 `pCx011010X3uzu -oi!cfs-pCmdoini(3 `p(itiaciopi6r7p-o4s-pcluodopk3 lAtmtio7u-ands-ikmdopk3 1Xxagoia,couzu-o.r!ds-IX-IneriorCa li(itiodoio/Couzu-oi!ds-pCinciopXa liculpipzu-onds licInctopico `1Xpliodld-posnj-TXxoqopicouzu `Licxotioloicouzu-posnj-pcxogoloicouzu .. oz liciuodop/C3uzu-posnj-ii(xotiopiCauzu liCumpozu-posrulAxoqojoicpuze IX.ppaci!cl-posnj-pCluodopiCouzu liCxogoiD/Couzu-posnj-pCluodoioiCauzu `pciuoclopiCauzu-posnj-pCwociopiCauzu liculmozu-posni-pCluodolo/Ouzu lAppoct!d-pasnj-pcu!pport `tiNNoinicouzu-rostij-pcu!mlozu lAltmdoprOVZV
-posnj-IALiwpozu licuwpazu-posni-IXu!mpzu licppod!d-posnj-pcxoqo3X3 ST
`1Xxoliopicauzu-posiglicxoLioloXa cpCluado loX3uzu-posnin /Nor...Top/0 IiCu!ppozu -posny-pCxotiolaXa lAppocild-posnj-iXworknoAD lAxoqopAnzu-posnj-iAluodoioXa licluodop/Cauzu-psnj-IXTmdopiCa µIXTimpozp-psnj-I/CluNlopico µ14!.md!d -posnj-IX1ncioloica IAxagoloXouzu-pastm[XingoioXo IXTuodoioXouze-posnj-IXpiclopiSa licuippzu-posnj-pcingoloico licpliod!d-posnnrcdoidolorc3 IINOLE010/caUZB OT
-postmiXdoiclopico `1Xwodopicouze-postmlicdoidoloica `pcumpozu-posnj-p{doidopic3 Joziai cpctozupl IiCtr!ze.vCd i/CuyILupiCd `pfu!zeppiCd liCpp/Cd lAjozumut! IATozuJAd `TAionAd `pCufzundld `1Auflogthout lAppocfild IiCluodolo/Couzu IXtilp!we `p(xxlopiCa-al!ds-p(cfardopi(3 `IXTuodolai(3-o.r!ds-1,(dardopi(o 1,01qopiCa -ca!ds-licdOidalOrco Iicxatiopico-ar!ds-Licxagolaico `pcxottoloXo-oi!ds-fkitiodoloXa licluodopico-w!ds-pcluodopico `1Xxogoloito-oi!ds-i Xingolo1c3 Ticmdoloico-onds -pcinclopicn liC1nclopico-os0s-pcincloric3 IX-ymicipX3-psnj-pCdoidoriC3 lkit.mdepiC3 -posnj-IXdoidoiDiCo liCinclopXo-posnj-pCdoidopiCo IiNogotoiCo-posnj-pCxatio-piCa licxoqop/Co-posimiXwactopiCo `TiCiu3dopiCo-posnj-pCluodopXo `pcxoqopiCa N
azacyclohexyl-spiro-piperidyl, 0 , preferably a substituted or unsubstituted bond, phenyl, naphthyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, piperidyl, morpholinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, azetidinyl-fused-azetidinyl, azetidinyl-fused-azacyclopentyl, azetidinyl-fused-azacyclohexyl, azetidinyl-fused-piperidyl, azacyclopentyl-fused-azetidinyl, azacyclopentyl-fused-azacyclopentyl, azacyclopentyl-fused-azacyclohexyl, azacyclopentyl-fused-piperidyl, cyclohexyl-spiro-azetidinyl, cyclobutyl-spiro-azacyclohexyl, cyclopentyl-fused-azacyclopentyl, azacyclohexyl-fused-azetidinyl, azacyclohexyl-fused-azacyclopentyl, azetidinyl-spiro-azetidinyl, azetidinyl-spiro-azacyclopentyl, azetidinyl-spiro-azacyclohexyl, azacyclopentyl-spiro-azetidinyl, azacyclopentyl-spiro-azacyclopentyl, azacyclopentyl-spiro-azacyclohexyl, azacyclohexyl-spiro-azetidinyl, azacyclohexyl-spiro-azacyclopentyl, azacyclohexyl-spiro-azacyclohexyl, azetidinyl-spiro-piperidyl, azacyclopentyl-spiro-piperidyl, or ; which, when substituted, are optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br, 1, OH, NH2, oxo, C1,4 alkyl or C1,4 alkoxy, preferably substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, CI, Br, I, OH, NR), oxo, methyl, ethyl, isopropyl, inethoxy, ethoxy or isopropoxy;
Cyl, Cy2, Cy3 and Cy4 cannot all be a bond;
when Akl , Ak2, Ak3, Ak4 or Ak5 is 0, they cannot be directly connected to B;
when Ak 1 , Ak2, Ak3, Ak4 or Ak5 is not a bond, they cannot be directly connected to one another;
when 3 of Cyl, Cy2, Cy3 and Cy4 are a bond, at least one of Akl, Ak2, Ak3, Ak4, and Ak5 is selected from CH2 and is connected to B;
when 4 or more of Akl, Cyl, Ak2, Cy2, Ak3, Cy3, Ak4, Cy4 and Ak5 are not a bond, at least one of Cyl, Cy2, Cy3 and Cy4 is not piperidyl, piperazinyl, Date Recue/Date Received 2021-09-09 pyrimidinyl or pyridyl;
N--, (Rb3),,i i H2NI s) (Rb2),,,, -'`- c-j,N _ N, B is selected from or''). , preferably = , i N
( Izinni2 0 Ni5'Lsrj N
r---%_-NH
or B can be selected from ',.=,---li =
, 9, 4 N-H2N-I s;) e----N-N
N., r-N4-0 , - NH .1'4.:1n _ NH
or B can be selected from N..,----9 or =
, 5 Rbl, Rb2, Rb3 or ICr", b4 is each independently selected from H, F, Cl, Br, 1, OH, NH2, CN, CON 112, C1_4 alkyl or C1_4 alkoxy, preferably selected from H, F, Cl, Br, 1, OH, NH2, CN, CONH2, methyl or methoxy; the methyl, methoxy, alkyl and alkoxy are optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br, 1, OH, NH,, CN, CONFk, C1,4 alkyl or C1,4 alkoxy, preferably substituted with 0, 10 1, 2, 3 or 4 substituents selected from 1-1, F, Cl, Br or 1;
n9, n10, nil, and n12 are each independently selected from 0, 1,2, 3 or 4;
(R")õ, _ Rk3 r ),,2 (F3'1),,, (Rk34,2 ( R'7 K is selected from 0 0 µRk4 or N 0 'R" , preferably H

---:---. --1( rr-L- 0 1\1-C 0 0 0 or , , (Row o (Rio)p, 1------:,-/'( -A _______________________________________ .---1"-----:.----\ _ c _ I:
"" ___________________________________ ""--- ----- NH 1-..,.....z.--------N
NH
or K can be selected from o 0 0 0 or , H

(ROpill r(-------'''N
15 N-- , Date Recue/Date Received 2021-09-09 or K can be selected from 0 o , H
0 0,.... N
--- ---1----c )=0 L
."=- N--C-----';----.\c NH H- 00 or i o N¨c-0 N----7)7__ -\\O
'N. NH NH
or K can be selected from 0 o , 0 0 , NH -.. 1/ _.\¨NH NH
0 ¨{Ni-Z ./,C) F F F '-µ

....Z¨NFI F NH F ....Z¨NFI
N tO NI.- tO N tO

i 11.1 ? I:) -i-hl "\ N¨cr-Nvi 0 NH N4 0 11----\
ii¨ N
N ----c ---0 '---------------\( NH
7' 0 a 0 0 0 0 0 0 , , , H

T.,_____,---- H
(:)''',""" N T0 0 H

1.-- , N --r----,--)--- ." ----. N---.----- --- N--."-----"r or ''' N

/

NH
\ \C NH F -\( or K can be selected from 0 o , 0 , -NH
NftIii-- 0 N 0 Ni.- 0 H

0 0.----'-r N'',----9'0 N N.--)---\ N-57¨N1-1 0 0 0 ___________ 0 0 or It' is selected , from CH2 or C=0;
Date Recue/Date Received 2021-09-09 Rid, Rk3 or R" is each independently selected from H, F, Cl, Br,!, OH, NH), CN, COOH, C1-4 alkyl or C1-4 alkoxy, preferably H, F, Cl, Br, I, OH or NH2;
pl or p2 is each independently selected from 0, 1 or 2.
Some embodiments of the present invention relate to a compound represented by general formula (I) or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein N
\ \ - - -N
-µ7( ( \--------/
L is selected from / N N-i-/ ¨N
_N 5 _N /
1-c\N4 c N ______________________________ )CN-1- _____________ \
=\ ( N¨

N-z-/
, N
_____________ )__ \ s \ N Nt \
IX ______________________________________ N __ CN 1 ( \N ( (/ \N-1--N / / /
, CN ____________ ( \N ( \N

, ________________ / __ / ___________ , -1-( \N \N \N 1 CN K ____ \N ( ______ \N ( \N i / ____________ \ __ / \/ /
, , N_CNA- N-0-1z- i_N
p----- -\---4-µk:7\N
_µ.._N---Ci ---CN-, or , , A--NN,,,r_NN....) 3c\..--- NI-, 0 ---µ--/
-i---CN---0-0-or L can be selected from F F F
(trans (cis) F, \
---"\N-_, N ______ CN-I-.
Date Recue/Date Received 2021-09-09 \ \ _____________ \
=I--= 7¨N-1- $ i = ( 7 CN-1- ii= __________________ /N-, \
-1-001¨CN1- _______________ ( \N¨CN¨CNI-/ or , 5 -1-0CN¨OCN-1-or L can be selected from -µ-( _________________ \1N- -F ________________ , H H H
-FC-N¨OCN-1- -K::N-==<=N-1--KLN¨OCN
H H H
, _______________________________________________ 5 , CON--CCNI- -1-N-OCN1 1-=CN-c-)=CN1 H
_________________________________ N-QN µ i 3.1 __ CN 1 -1-CrN--<N1-H
H
-KN---CNII--FCCN--CNI- A-CN¨CN¨CN-1-H or 1-CN-CCNi-, L is connected to B on the left side, and is connected to K on the right side;
B is selected from Nti2 N HN
"- =N N^- =N
i i 0 -- N
H2N- N H2N" ``= I
pi---CN-1-N 1 , , N
O

,._. i 40 Cl...0 ...'s N
---.. ' 0 r;e or 11N , "4-) N

, N----:\
I N

(Rb N,---',N
%4 N
H2N N= 1 \I _e1(R64).4 N--C N+ N
--N' or B can be selected from / 141 0 -'`
Date Recue/Date Received 2021-09-09 N---- \\
H2N i , a---N H2 H N._ , N
S

----(Rh4),E5 N
x or '...=---1-1 , R1'4 is selected from H, F, Cl, Br, I, OH, NH2, CN, CONH2, C1-4 alkyl or C1-4 alkoxy, preferably selected from 1-1, F, Cl, Br, I, OH, NU?, CN, CONH2, methyl or methoxy; the methyl, methoxy, alkyl and alkoxy are optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br, 1, 01-1, NH,, CN, CONH2, C1-4 alkyl or C1-4 alkoxy, preferably substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br or I;
n4, n8, and 1112 are each independently selected from 0, 1, 2, 3 or 4, N-<,,, ,\N b 0 \ / =N-N,õ---LI
--. , ___________________________________________ N
a õ-,,, or B can be selected from ' 0 H2N- _\
H2N N_Th\ H2N N,\
\ 2 N
\ / N \ N
/ E
- F -C5 \N-N
-....,.õ I \I_ r-N__.-,_, H2N 1 N,\ N,_ \
\ / N H2N H2N
F F
N

1 , 1 P
0 NI ot .. A, c . = N
N --¨N ';';- .1_ ---- N NH2 Ni/- ) H2N \ 11 01µ--)---1 HNN¨Y"' NH
N , N

N---\\
cA. _./NFI2 FAN
N% -`=
-;-,-ri 4.L...0 ,.. .
N N __________________ ) 1...)... gib -'1µ1' N
e.....- 0 'IP
N r-N)).....NH \ 1 t--------0 ,-,,,- or =.=.--u =
Date Recue/Date Received 2021-09-09 H

- N-c-fr'''-----\N-c_ 0 r --"-= N------------'' NH (-,------- -_.\ NH ----' ,..- ...-K is selected from 0 0 , 0 o or N' /
(Rki )pl 0 (Rk1)0 1 c -_,D ri--\

NH NH
or K can be selected from o 0 , o 0 or H
0 N,0 0 "'"-----. ----(Rki)piii d-."'-----N:--z¨Ft R" is selected from H, F, Cl, Br, I, OH, N112, CN, COOH, C1_4 alk.y1 or C1_4 5 alkoxy, preferably H, F, Cl, Br, I, OH or NH2, pl is selected from 0, 1 or 2, 0 o N, iZ N N

-**-=-!---- ----cNI\T
N
or K can be selected from /
H
o 0 N 0 0 o or I o N¨cNH 0 NH
or K can be selected from 0 0 ic j.\--NF-2L 0 ic,.\--il 0 c.. ---Nli-ic) &N-Z-1\itil 0 ",zµ
F F F" - AK
10 0 , 0 , o 0 , ...Z-NFI F NH F 4¨NH
N tO Nw-Z-- tO N 0 A A A

, , , t ---\N N 0 NH
N-- 0 - I. -----c --- ---\.c ---cNII 0 -\ NH

-r 00 00 0 o 0 0 , , Date Recue/Date Received 2021-09-09 H

N , 0 (D---,=---NT
N va. ii-NT----T
-, N------N-----L, N.:;..1.,..
or , 7 o 00 \ NH
N¨clC) N ¨Co \ 'c NH
or K can be selected from 0 0 , o 7 NH
N., NI¨(--- 0 , , 1 H

A ¨c.NH
Ci , o 00 or N
Some embodiments of the present invention relate to a compound represented by general formula (I) or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein _Iii¨N) N\._ \ \
i--( _________________________________ N---( __ NA- \------/
L is selected from / /
_N N
N / __________________ ..r.},PLK2r/
--1--c /),---N \N-1- N 1-c ,) _ K N - 1 - N-<NI-N / \
, / N
N
N)-- N-1-_______________________________________ N N1 IX \ C __ 4 __ ( \N ( \NI-/ / __ /
, N _____________ CN i i-CN __ (/ \NIX __ \\N
-IX \N¨( _________ \N¨( , \NI- A-CN-( \N-( \N-( \NI-/ ___ / 1 / / 1 , OA- "c1,....,N\N
p----CN
or 7 7 r'Oc.
'X
.--\;.---N N1-' Date Recue/Date Received 2021-09-09 X
0 --µ""N
;
\

or L can be selected from F F F
--F6 (trans) (cis) F, N N
F,\ E_ Fi af---( j\N¨CN+ li = ( I\N¨CN if ( ;\N¨CN-1.- .. -1¨( __ N

\
-I-OCN-CN1- i K _______________ 7 __ CN __ CNT , 1--CN--( or or L can be selected from ______________ t,--0-+- - N-CN-1-, H H H
N ______________________________________________________________________ (----N
H H H
H
-1-0CN¨OCN-V i 3 CN 1 --1¨CION¨N1--H
H
, I-CON ___________ CNI- .--I-CN--N-- , N+
H or KN¨CON-1-.
L is connected to B on the left side, and is connected to K on the right side;
B is selected from mi2 HN N-;--N-N N,---NN
H2N-Lr H2N-..... ,N---041-= .............................................. ---N'N¨S 1 N
a .....,:cj = 1 Ne---,0 gi-tipp N
, or Date Recue/Date Received 2021-09-09 N , N
--/ N( -N.
N\ NH
, N,--"=NN
(Rnn4 H2N N 1 i __ \
/----or B can be selected from __ -144¨<-Nt 40 o , HNi,._ N'''N 0-H2N N1 r \. I,., N

--- = (R.64)n8 N
X or , N

, N
0 r--- , '.----...,..._/
Rb4 is selected from H, F, Cl, Br, I, OH, NH2, CN, CONH2, C1-4 alkyl or C1-4 alkoxy, preferably selected from H, F, Cl, Br, 1, OH, NH,, CN, CONH2, methyl or methoxy; the methyl, methoxy, alkyl and alkoxy are optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br, 1, OH, NW, CN, CONH2, C1-4 alkyl or C1_4 alkoxy, preferably substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br, I, n4, n8, and 1112 are each independently selected from 0, 1, 2, 3 or 4, N._---, H2N - \
N,--"-NN
F
H2N N i ¨ =
--(---) --- N
_......N.,, or B can be selected from 6 k"-----)--0 N,-_-_--, I-12NiN H2N
H2N N_-_-_-,.\
\
F \ ,N \ , N
F F

N` ""-----) (trans) (cis) Date Recue/Date Received 2021-09-09 N-_,_, N-_-,-_\
H2N , -1 H2N , 1 H2N
\
\ / N F
__ 0- \ / \N-N,,,,,--:....1 o' -.........õ..N,s.. dr. --........õõN".... a ---...,..,,...
/
*
0,0 cNi_ (---N--,-, -N -21,.. '--- N NH2 / \ 1 ) , ...0 H2N N \ CO( ..--- H2N _ I N =-. N HN\____ j NH
.'"

N -=."--- NH2 \N N-) EiN

H2N-j' --- /--N.
=

_______________________ illi 0 N N
.1111111-47.
N
or , , o NH 1101 -- \KN---)/-Nti K can be selected from o o 00 .õL..., 0 0 NH NH NH
No 0 , 0 0 0 , ,..Z-NH
tO N 0 t ----.. JOIN NH 0 "? N 0 0 N

NH N-5)-NH
-r 00 00 o o 0 o , H
0N,0 H
0 .----- ----- 0 N,. ,,-0 H H
0 T......:" 0. N , 0 S

----'"-----' 0 1\J() 0 N
N'''.-, A- -N' ."-- or , \--- NH
\ N-5,_ 0 N 0 NH F
or K can be selected from ' 0 0 o , , Date Recue/Date Received 2021-09-09 ,...,N F.t F NH
NH
Ni.-. .0 N . 0 NI¨ .0 o 0 0 , , , H
00 0.,õ
0 ,N, --0 --4.- ---..--1--õ.õ..---A N I
0 00 or N--N
Some embodiments of the present invention relate to a compound represented by general formula (I) or a stereoisomer, a solvate, a prodrug, a metabolite, a 5 pharmaceutically acceptable salt or a co-crystal thereof, wherein / _________________________________________________________ N
\ \ 1 -X
¨N\N --1-< ( - \..--------../
L is selected from / N N--/
)C N-- ' _N _N / .,3,-, ( \
-1-c /)¨N \N4- 4-e )¨N i \ / , /N¨CN1-\ N / N `
/ N Nt N \ s ¨It 1-K \N¨CN-i-(\NI-/
iNi- -N NN-N-<- \N¨CN-I-i \NI- A-CN4 \N¨( \N¨K \N-1-10 _________________ / / / /

.3p r-_-_-N
NCI or ---C\N-._ , , N 1-NNk kerN,...__J
-N Nt -t--0---N--ic;'X 0`X.
, )(CN
, or L can be selected from Date Recue/Date Received 2021-09-09 F F F
-'5.' (trans) (cis) t-IN N N
-1--< _________________________________________________________ \N-CN I
+-( I\N-CN+ f i = CN-01-1- ,I\N-CN+ ____ , \
-N ______________ CN K __ \N __ CN ____ =CN __ or CN--( \
-%-( IN-01-or L can be selected from -F-OCN-<>CN-i--1--5 , H H H
-CN I-- -----OCN icic N¨CN-E
N -E-OCN
1-CON--CCN+ -IN-OCN-1- -i-CN-OCN-1-H
N
H
H
1-CON ___________ CN-i N ___________ NN-- I<N¨CPµii-H or -FCN-CCN-F .
1 is connected to B on the left side, and is connected to K on the right side;
B is selected from 0, 0')'-'-''-C r N
N
or N--õ
H2N i ) N

/ N
--- ---() N
r \_--=N
__S , Date Recue/Date Received 2021-09-09 Ns-'"=K: Nr--.N.
N
{Rb41 \
H2N N A H2N \ A, _01 ¨ .N¨( N+ N
--. .
N /
or B can be selected from 4111 o , 401 o , N¨

HN
,., ,N
a -cy'',---N)--(Rb4).$
N
'\=,_) re or , Rm is selected from H., F, Cl, Br, I, OH, NH2, CN, CONH2, C1_4 alkyl or C1_4 alkoxy, preferably selected from H, F, Cl, Br, 1, OH, NH2, CN, CONH2, methyl or methoxy, wherein the methyl, methoxy, alkyl and alkoxy are optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, 1,, CI, Br, I, OH, NH2, CN, CONH2, C]_4 alkyl or C]_4 alkoxy, preferably substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br, I, n4, n8, and n12 are each independently selected from 0, 1, 2, 3 or 4, N, N-------NN H2N , - \
\ / N
H2N \ A F
N¨CN-1- 0 N--1 n \N_ or B can be selected from ----)".-o 0 H2N N:_-_-\
N, \
H2N -1 H2N /N \ /N \ /N
0 \ N -N' ".----------i (trans) (cis}

0 , N, H2N- N__-_-_\
N, H2N , / N
---( C ---( F
0 \ Nõ 0 " = 0 \N -N, ...õõkõ,1 0 \ N, N )1 -...,,..N/... O -N,_ / \ , Date Recue/Date Received 2021-09-09 0,,, 0 0 Nr%
N --r--" ,N
N ---H2N Hzi\J
HN \\.5 NH
0 0 )----/ 0 N
N--....,", 0 NH, N---\\

N
Ca-0 N

'C' _N
N f.-- ,.¨NH
,e' or ''..,--u =
o 00 NH

\ NH F
K is selected from 0 0 o , ' N., ZNH
--- 0 N (:) N",-,(:) 0 o o , , , H
00 0.,õ
0 ,N, ..0 --.¨ ------N 0 N0 N---"---""
0 0 o or N
Some embodiments of the present invention relate to a compound represented by general formula (I) or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein / ___________________________________________________________ N
L is selected from NI-/ / , _______ ¨N , _N \ 5 -N
_________________ N1- -4-C .---.N/ _______________ KNI- ( \N¨C Ny N /
, \ N \ _______ , _______ / , , __ N c 1¨( \N¨CN1- 4 _________ ( \N-( N --\Nt \NI---N / __________________ / __ /
, \
N 1--CN ______________________ ( \N--( \N¨CN1-/ ) /
¨1¨( \N-( ________ \N¨( __ \N-1- --.CN-( __ / \N¨( \N¨( \NI-/ / / / /
Date Recue/Date Received 2021-09-09 N NI
l'Oc.
x i-C)----N3___(-X. 0 .._ , ' , O-CN-1- -i-N---0--8 or L can be selected front =\- , F F F
-'''''---k r__--\ (trans (cis) F
N,\ N,\ \
\_.- NI \õ-N4 V- .N 4 __ if < 7-CN
i_ \ \ \
-1-- 7N ----CN-f $ i = ( ___ /N-CN-1- 1- __ /N--0-1- N-CN-f , -1-0CN __________ CN CN __ CN __ =CN1- -F-CN---( \iN3c.
or A N i C
C \ -01- --ON-ONI-or L can be selected from X ___________ i _______________________________ , H H H
-1---CN-(0=C\iNi-- N4-H
+-CON -00+ 1-CICN¨C: ' H H
+CON¨CON+ -FCN-OCN-1- -i-CN-OCN-1-H
-k-OCN--OCNV i N _____ CN I -i-CN-CN-1-H
H
+CON ____________ CH- -1-N-N-CN-1- -1-01.-CriNt H or -1¨CN¨00\11- .
Date Recue/Date Received 2021-09-09 L is connected to B on the left side, and is connected to K on the right side;

B is selected from N-=-::-\N
H2N- \ / \
NI-/
N ______________________ . 0 =
, N ----"=\ N (Rb4)14 H2N-----k 1 \
,N¨( r3----or B can be selected from o , 5 Rb4 is selected from H, F, Cl, Br, 1, OH, NH7, CN, CONH2, C1_4 alkyl or C1_4 alkoxy, preferably selected from H, F, CI, Br, 1, OH, N142, CN, CONH2, methyl or methoxy; the methyl, methoxy, alkyl and alkoxy are optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br, I, OH, N112, CN, CONH2, C1-4 alkyl or C1-4 alkoxy, preferably substituted with 0, 1, 2, 3 or 4 substituents 10 selected from H, F, Cl, Br or I;
n4 is selected from 0, 1, 2, 3 or 4, N-.----\N H2N -1 \ /NI
_ , or B can be selected from 411 N / b o , , H2N Nz-_--\
N,--_, \ / N H2N , I N..-,-, 0 \ -N
N
(trans) N- ===-="Th = N (i ...N,...
, N1,-._, H2N N'-----1 F ----( F
, 0 \N-N 0 \N-NI''=)') c5. L.,N, a, -..,_,Ni..
or H
0 00, _N._ -.0 ------ ""
______________________________ c¨c-0 --1---¨c_ OAN
1--õ_,:-.---= \K
NH NH FLL _.,_ l' eL-15 K is selected li-om 0 o , 0 o or , Date Recue/Date Received 2021-09-09 (Rkl)pl 0 (Rkl)pl 1 6-1-1c-V--0 A

NH
or K can be selected from o 0 , o 0 or H

0 ---- --,;(=-(ROpm I¨

N- ---=- , RH is selected from H, F, Cl, Br, I, OH, NE11, CN, COOH, C1-4 alkyl or C1-4 alkoxy, preferably H, F, Cl, Br, I, OH or NH?, pl is selected from 0, 1 or 2, -I ________________________________________ ! N 0 --- -' NH \ /0 or K can be selected from 0 o , H
0 N....0 ------1---n---'N a --.. N"----------NH
0 0 or N , N¨c 0 ----'''-----I N--c-0 NH
'----!--\( NH
or K can be selected from 0 0 , 0 0 ' F Z
i.,¨NH
N-NH N_\---NFI 0 N.,- 0 'IL
- µ F r o o o 0 4_Nil N 0 [VI- Z--- tO N 0 0 , 0 , 0 , / ----N

N¨cNH N¨cNH 0 N 0 H
0õN 0 H

0 "õ.5 H H
'T...:

---, N

or rel-, 7 Date Recue/Date Received 2021-09-09 NH
\ 0 --"\-(N-c-NH F
or K can be selected from 0 0 , o __ ' O0 _Z--Nht NH
NJ,-H

0 Cky N-....0 N 0 N r.?171 0 -µ
0 00 or N

Some embodiments of the present invention relate to a compound represented by general formula (I) or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein N
-1---<¨ --f\l/\

i-K \N--( \NA
L is selected from / / N
_N / \ 1- s _N
5 .f.,,'' - ________________________________________________ /)¨N __ N c /)¨N1/ )CN1- \
( \NNI._ ' ________ N N \ i , N
)--N
N1- -F( \N _______________________________________ CN 1 4 ________ (\N-1--N i / /
, , ________________ , CN-( _____________ \N -----CN-- -- __ \N
/ /N
-F( \N _______________ ( \N __________ ( \N-1 t-CN __ ( \N----( \N ( \N-i-/ _______________ / / / / / , N p-CN-CN-- _N
---C-/N---"CIN.%-- ----CN, / > /
r\OC, Ni -i---"0----_ '1X._ GI'J0X
A.--/
N
, Date Recue/Date Received 2021-09-09 ---\-C N NI
tf-----/ -1-CN-0---or L can be selected from -`2-F F F
(trans) (cis) -'555-aN N N \
---ON 4 -i-( /N-CN-1-\ \
ri-- i\N-CN+ 'i==( /N-CN-i- It = ii\l-CN+ -1-0CN-CN1--,-OCN __________ CN i K \N ______ CN 'N1- \
CN-=( or N4-, / =
, A-C,i-\N-<:>--- \I-or L can be selected from -1-0( /N-C>C\N
, H H H
tcicNiNf +CON-CON+ -N N1-1-CN-OCNI-, H
-FOCN¨OCN-µ- i N CN-i- -1-C-N¨CNI-H
H
-1-CCN-CN-1- -1-CN-CN-CN-1- 1¨CN¨(tNi-Fi or , CON
.
, L is connected to B on the left side, and is connected to K on the right side;

B is selected from H2N- N I _c) N
--. =
N
/
Date Recue/Date Received 2021-09-09 "tc H2N x¨N
N
7--(Rb4)n4 or B can be selected from I 0 R" is selected from H, F, Cl, Br, 1, OH, NH2, CN, CONH?, C1_4 alkyl or C14 alkoxy, preferably selected from H, F, Cl, Br, 1, OH, NI-12, CN, CONII2, methyl or methoxy; the methyl, rnethoxy, alkyl and alkoxy are optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br, I, OH, NH2, CN, CONH2, C1-4 alkyl or C1-4 alkoxy, preferably substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br or 1;
n4 is selected from 0, 1, 2, 3 or 4;
or B can be selected from N N

k ________________________________________________________________ N
NH
K is selected from 0 o o o or N-(Rki )pi 0 (Rk1)p1 ir-NH
or K can be selected from o 0 o 0 or 0 0'-'N'"C--0 s Ricl is selected from H, F, Cl, Br, I, OH, NH2, CN, COOH, C14 alkyl or C14 alkoxy, preferably H, F, Cl, Br, 1, OH or NH2, pl is selected from 0, 1 or 2, 0 0 rt,:yo s>s' ---rN.1\710 or K can be selected from o 0 0 Date Recue/Date Received 2021-09-09 H

0, _N0 `----- -----i 'r--='-'-'------\
Q;¨c 0 Lr-ILE\r' NH
0 0 or . ----- -A
µ`o NH
or K can be selected from 0 0 , 00 , 0 0 ,/,( --NH
N.\--NH
(2) N\-- 1-., 7 NH _\>\¨
N. (:) 0o N
--z F F
o o 0 o ...z_NH
A A A

N¨ 0 NH N¨cNH 0 -\N¨cY
N----NII A
5 1¨ 00 , 00 , 00 H
00N_ õ..0 H
--,-- ----- 0 00N0H H
N 0 e,....,:i N 0 , 0 0 N

N
iiii JL I
.;,--J.,.... N ¨
N i or III" N")----, , 2.( \--- NH
\ Nj>/¨NH 0 F N¨ 2-0 or K can be selected from 0 o , o , NH F NH
kNU,.----NI, -/..10 H

0 ..-- '''',------F 4¨NH 'Al N ,C) N¨c 0 N--'-'--õ.,.-..1õ, 0 00 or N .
, 10 Some embodiments of the present invention relate to a compound represented by general formula (1) or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein Date Recue/Date Received 2021-09-09 N
--TV/--\
-µ--( \N--(N-1-L is selected from / / ¨N
_N __ \ /
f\i/)_N( __ \N 5+ 5 c /i¨N KNI- 4:\v ( \N¨CNI-/ , Ki __________ N \
)----N \
NI-- -IX N¨CNI- 4\444\----( \N¨ \NI--N / / /
\ õ "
Ni- -1N-- \N-- \N¨N--1-__________________ / /
-F _______ \N---.< __ \N--( \NI- -t-N¨( \N¨( \N¨( '\NI-/ / ___ /
N--CN- p----C,/ --\----(µN
A____N-----0 -----0.-r-----µNk NLT___N\__J
X
N-1-- -i---0---N\___.
.,..N
, tx------1 1--CN-0--or L can be selected from A , F F F
N,r_-\
V-N..1 V-N
, F E. F
\ \ \
7..- 7 __________________________________ CN-1- t ( 7-----CN-1- it 7 __ CN-, 5 --,---(CN ....................... -CN-i 1 CN =CN -FN -1N--4- \
-C--( N34--or , --µ \--0-1- -i-OCN-OCNi-or L can be selected from il Date Recue/Date Received 2021-09-09 NCN*_K-jcNNf CN+
¨Cr3N--r +CN¨CN¨CN-1-or =

L is connected to B on the left side, and is connected to K on the right side;

B is selected from NH, HN
0 7_1,1 I
N

,N
S)-(Rnna a 0 or B can be selected from =
R" is selected from H, F, Cl, Br, I, OH, NH2, CN, CONH2, C1_4 alkyl or C14 alkoxy, preferably selected from H, F, CI, Br, I, OH, NH2, CN, CONH2, methyl or methoxy; the methyl, methoxy, alkyl and alkoxy are optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br, I, OH, NH2, CN, CONH,, CI _4 alkyl or C1_4 alkoxy, preferably substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br or I;
n8 is selected from 0, 1, 2, 3 or 4;
Date Recue/Date Received 2021-09-09 a_ ---. 0 --- N
H2N \ 14,, CN1"
or B can be selected from FIN\_-/
' , H
0, N 0 0 0 .."---. '-"r----N---c t" n-N-(\.,/- 0 NH ,-.-%----\K NH ---1J_ ,..-_-_ --I
K is selected from O o , o o or ------- -r\r"
(RIO )pl 0 (Rkl)pl ¨kL-I''''''' ---jc----c 0 NH
or K can be selected from o 0 , 0 0 or H
, 0 0--'1\i0 (Rki /pi II
-1¨

LIN,,, ...).1.µõ..
N , R" is selected from H, F, Cl, Br, I, OH, NH7, CN, COOH, C1-4 alkyl or C1-4 alkoxy, preferably H, F, Cl, Br, I, OH or NI12, p1 is selected from 0, I or 2, or K can be selected from o 0 , F /
H

t _________ _ N----i- 0 5__Lr----)LN
NH Q ___I
0 0 or ------ -N---"- , C) N-cNH 11 '...42,1_ 0 \K
--"' ----\ N/H
or K can be selected from 0 0 , o 0 , _Lõ 0 0 JIcN==

NH NH NH
w __ tO
N -.\--- 0 N -- Z- 0 F ---\ F ----\K F ----- -;?-c Date Recue/Date Received 2021-09-09 ....Z\--NH F NH F .....Z\--NH
.--- (:) N

, , , , N-i---NH 0 N¨c 0 /IS N---i___ 0 'h--------\N 0 'IL NH -i NH
----..õ:--------\( NH
i 0 0 0 0 0 0 0 0 r , H

H H
0 OIN2:0 oN N 0 , 0 0 ,N 0 N
e, N
i I
or , 7 NH
N< __________________________________________________________________ )=o \ ----t¨H---0 F
or K can be selected from o 0 5 o ' .._Z _____________________________________ NH F
NH
NI- 0 N 0 Nit- 0 0 , 0 , 0 , H
00 0-._ ,N._ õ...0 0 ----,- ----0 N¨c 0 N----'-"-0 00 or N
, Some embodiments of the present invention relate to a compound represented by general formula (I) or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein N
.
\--------./
L is selected from / __ / NA N
1-<'IN
, , \
-0( N4 A c Ni)¨ N/ __ KN-1- ( \\N CN1-/ t N
(./ ________ N)\ N--- 7+ IX \N¨CN-1- 4 _________ ( \N _________ ( \Ni / / / , CN ____________ ( N4- N ____ ( \N ( \N tN11-__________________ / _____________ / ____ / , Date Recue/Date Received 2021-09-09 1-( \N¨( \N¨( \N-1- -1-CN-( \N¨( \N-K __________________ \NO-/ / / / ___ / ___ / , N----C
N GNI---\--- ________________________________________________ \N
---ON--X
N r\Nk N-1-- -i--0---N 'X
--\_-,--N 0 OX
_ , ----\N----CN1-5 or L can be selected from -V----/ 1---CN-0--(3 F F F
/N¨CN-1-f< /\N _______ CN-1- i' ( i\N _______________ CNI-1- ii.' /\N CN-1- N
CN
, \
-i-OCN¨CN1- ________________________________ ( N¨CN¨CN4- __ -\
N---( N-i-or , i or L can be selected from \N-0-1- -1-OCN-OCN-1-/
H H H
-i-C-N¨OCNi-N¨OCN i 1-Cl:CN¨00 H H H
1-CON¨CON ________________________________________________________ --CN-OCN-1-, H
-FOCN-OCN-µ- 1 G ______________________ cNI
-C

H
1--CON-CNI- -1-CN-CN-CNI+ -1---N-----1-H or Date Recue/Date Received 2021-09-09 L is connected to B on the left side, and is connected to K on the right side;

B is selected from N

µN--1 Ci-NH
N--\\
H2N-1 \,) 0 = INI-'r(Rb4)"12 or B can be selected from Rb4 is selected from H, F, Cl, Br, I, OH, NH,, CN, CONH2, C1-4 alkyl or C1-4 alkoxy, preferably selected from H, F, Cl, Br, I, OH, NH2, CN, CONH2, methyl or methoxy; the methyl, methoxy, alkyl and alkoxy are optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br, I, OH, NH2, CN, CONH2, C1-4 alkyl or CI,4 alkoxy, preferably substituted with 0õ 1, 2, 3 or 4 substituents selected from H, F, Cl, Br, I, n12 is selected from 0, 1,2, 3 or 4;
NA
N

/ or B can be selected from 0 NH

NH
K is selected from 0 o o or (Rkl )p1 o(Rkl)pl NH NH
or K can be selected from o o 0 or Date Recue/Date Received 2021-09-09 H
0 N".--.7"C) (Rkl)pill , Rd is selected from H, F, Cl, Br, I, OH, NH?, CN, COOH, CI_4 alkyl or Ci_4 alkoxy, preferably H, F, Cl, Br, I, OH or N112, pl is selected from 0, 1 or 2, or K can be selected from 0 0 F 0 H

E _______ 'r k----\-cir0 f------it-0 N\I
NH 'FL
0 o or N--- , 0114N4 o 0 ---\.(1-i-Nhl 0 ir--NH
or K can be selected from 0 0 , 0 o , --- -. 0 0 NH NH ---.NH
N---- 2-0 N----Z 7=0 -----...
Z
I N NI I

No 0 F F F

tO N 0 -4'2=L -\_ --µ

t /
.------...-----\, _c \ ----lz"--,-.--N
N

I N )2, N-cNH NH
-I- 00 00 , 0 0 , 00 , H

01-'7f i 0 ",:---- 'f=
..:i,..õ
--- t4-:---1..õ
or NH

c 0 0µ
\--C-----7.--\( NH F
or K can be selected from 0 o , 0 , Date Recue/Date Received 2021-09-09 ,...,N. I-.1 FJc1Ii NH
NH
Ni-t .0 N 0 NI.- .0 , , , H
0 0 00,. , N, --0 --4.- ---.---N.. 0 -µ N¨cN1-1 0 õ...1..,..
0 00 or N .
, Some embodiments of the present invention relate to a compound represented by general formula (I) or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein the compound is selected from a compound represented by general formula (Ia) or (lb), R-Cy 1 -Cy2-K (Ia) B-Cy I -Cy2-Cy3-K (Ib) N---",-"\ N N----=`-N
H2N¨N I H2N N 1 r--N
) ¨ =
--N
lell ill B is selected from . 0 , 0 , N, NH2 H2N - \
HN t-i2NI- \ / N

IPN a . Nr -ir, 0¨

N
i=;'` or Cr\ , , H2N _\N_-, N.__ H2N 1 H2N ¨1 \ /N \ / N \ / N
F F F

(trans) (ms) = -...,,N, -"--/
, N,_-_--\
N¨, H2N-H2N- \ 7N F Iv \ 7 N
F
: \
60 it*
N
, Date Recue/Date Received 2021-09-09 cN,._ (---P N --o 0 o H 0 NH2 / \ N(/' =) )¨
H2NyZT-1=1 = -. " 2N \ N 51-HN
N , N or 0 -, , Cyl, Cy2, and Cy3 are each independently selected from one of the following substituted or unsubstituted groups: 4- to 6-membered nitrogen-containing mono-heterocyclic ring, 5- to I 0-membered nitrogen-containing fused heterocyclic ring, 6-to 10-membered nitrogen-containing spiro-heterocyclic ring, 4- to 6-membered monocycloalkyl or phenyl, wherein the phenyl, cycloalkyl, mono-heterocyclic ring, fused heterocyclic ring or spiro-heterocyclic ring is optionally further substituted with 0 to 4 substituents selected from 1-1, F, Cl, Br, I, 01-1, NH2, oxo, C1-4 alkyl or C1-4 alkoxy, and the mono-heterocyclic ring, fused heterocyclic ring or spiro-heterocyclic to ring contains I to 4 heteroatoms selected from 0, S or N;
or Cy 1 , Cy2, and Cy3 can be each independently selected from one of the h ___________________________________________________________________ N
following substituted or unsubstituted groups:
pl )c...4.,:!\
/ __ \
-r%.iN-i- ¨<N+N N-1... - N Ni -01¨

\_J
F F
1-N( \N4 -1-1.; Ni- 4-0CN-1- .--...õ.õ.õ. N --...õ... N .., F F F F
trans cis -1.--OCNI- ______________________________________________________________ N4 F
;"------1-1 -Ni- 1_N. ----_____, N , .' or , which, when substituted, are optionally Date Recue/Date Received 2021-09-09 further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH7, oxo, C1_4 alkyl or C1_4 alkoxy;
H

r-k----1( 1 r----N
-"It=-%---e-C) N-2-10 K is selected from ZNyl _.._0 \s"\--- N
\ / 0 or F .
5 Some embodiments of the present invention relate to a compound represented by general formula (I) or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein the compound is selected from a compound represented by general formula (la) or (Ib), N--=-NN N -r4, H2N N I _____________________________________________ 40 H2N N

--. =
N N
B is selected from 0 0 , 0 , N,_, NH 2 N--,,,, H2N -1 HN
N
0 "..-N11 ';,,, =,...__N ,s 10 r:j=;' or ...--1/
, , H2N N_,___\
N_-__:\
\ / N 112N INL-----\ 1-i2N
F \ z N
F \ N
/ F
0 \ N
(trans) N" 4.-------..) (ms) , N_-, N\ H2N.----___ 1N

___I= c / F
0 ii - N "
N" ''.---Th 0 a ---.._____ NA O
, Date Recue/Date Received 2021-09-09 cN,._ 01_0 (NN
p N -----14 NH2 / \ N// =) )-1H2NA-1,1*-0 H2 N \ 4 ON V
NH
NIN HN
or 0 -, Cyl, Cy2, and Cy3 are each independently selected from one of the following /---N
CN)--µ

substituted or unsubstituted groups:
V
)pN -- ...k. 1:,,,,..---1 , 7¨\ , \
+0\1+ N., NI_ r N Nt -1---)- TO( Ni 1-/
F F
Y
isofj1 ****-kl -1-0CN-1- -,¨OCN1-F F F F
Ii..., tran cts ......,,... N .., -,...õ.õ..N .... .,.,.N ,.,.1\1, 1 N-1- +CON-or a 00 1 o ---<
iN ,7--NEI F N.\----NH 0 K is selected from o o 0 0 o , , , NH - NH
_-/CeN___Z--N/H0 0 Ni.., Z- to F
-1) F
0 A.

....Z _____________ NH
i-0 N 0 0 , 0 , 0 /
Date Recue/Date Received 2021-09-09 i N-i---NH 0 N---NH 0 N---NH lai ---\(N)--NH

' 5 H

0 ".-"L "--7"

C) N 0 H H
0 0 N 0 0 01.11,y0 "--------N.-.1..õ. NI-N N
or o 00 00 Z----NH
1\4-NH
preferably A NH Fjc NH
fD

H
0 0N....,0 =,s5 N"-------.
N-i-N1-1 --;.1.,...
5 00 or N
Some embodiments of the present invention relate to a compound represented by general formula (I) or a stereoisorner, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein the compound is of the structure selected from one of:

N="---",N 0 f-T:
_ON .-- N,7 --. N r pµi, -0 i-i2N 1\ \ _1 / N
A aii\
N-C

N __INN- " -N

, N= /
1.
¨ 0 0 ,---- \ N
NH
N=-"--=
Ni NH
,N N If\
0 H2Ny _IV
N N N-CN-Q-NDC 11 --k.No 0 0, =00 -_____________________________________________________________________________ Date Recue/Date Received 2021-09-09 0_ 110 x PI H-2NõN
1 0 ct N-N
0 µ

N"

ON 0 NN___CRY-N

N*

'0 N.---,, -------------------------------- H2N N
N 0_ hi2NA, A C":- 0 ,I.2) ---cc ----N
"WN-CN-CN---CN N-N

0 ---r- 0 0 N L.> _____________________ --____4,,_1 N ______ \
..--....: c 0 \ ( __ \N-( N

0 / __ / o p i--\'N'N '''' V =
__LI,W04- N---1 0 * 0 0 N, _CIN ----1\11\i_CN---CN--CN 0 N
N,,,TrIR;LNH
N,_./N 0 0V 0 ______ N-C --CIN NtL'4F1 Q
NCNO 411 N:o-70 0. _CI
H2N FI,N4N..õ42,N
0 0 0 _________ p .0 -- N l'i N--n 0 N a .01 N'PrCIN
H,N N
- 0 'N
,.P4 N

H2N / \ N
H2N ,e/-1 N N--=,-(., NH N=1. .

p ----------------------------------------------------------------------------i N (---3 _f\-1, j.'N
N
N
0 / \ N

N N=2 N NH

Date Recue/Date Received 2021-09-09 p 0* .
o N
.0 H2N N 0 0.....-Frl_, ¨ 4IVIYL'/

Q0 ____________________________ 0 __, __C/N 0 =r4,N_õ0 õel H2N ö N
NH \ N \..-N

0 = N 0 0- = nR) -N-04 .........1,-'N.NO
H2N 4,7 \Sµl H2N-CN
o 0 0 0 Q i \
F'''.(R) j 0 N {5>
ID. = ,,N.,C7' 0 H2N / \ N
N-/ H2N ------H/ \ N
N=I
, H2N \\ , N
F
17., \ -- ...õ__-, N
,>=0 F _ F

Date Recue/Date Received 2021-09-09 H2N N..._\ N=,,, \ z N H2N \ N
F
-(/

,)--N 0 NH
= \ 2/-ll JNO 0 F 0 a * _Z---N- 0 i H

0 ,NGN- 'N 1 ___________________________________________________ \ ------ _A K \
N N--N---K. /N 0 -1:1H H2N-N -....,,N
N= 0 o 0 H

--- N
H2N NJ / \ N _CIN 0 0 0- .
N

N-,,/
9 = , --\
C/N --- ...,N0-t..70 -0 ..---! 0- 010 N`N CIN --/
".... _IN
=N__CN-CN-N *

N.-_-/N 0 NH _Z-----NH

___CIN' LIN
H2N -N 0 ________ H2N
--- __NoLiN
N / N i -N

10 CX * )c I

---- \,7.-- --- N
N NH 0 i ..---0 H2N \ N ,N
N N
FIN\ i _________________________________________ CN-CN -N

....--%, a I
"--, I
H.---0 1=1 0 0 N 0 "I.I
' HaN \ '.... N

N NI
N N __ HN\j,,,,,( N--( Date Recue/Date Received 2021-09-09 /-------' N,-_,,, H2N \ IN
,---i N' -0 0 r,_iiti0 N.-..N
H
0 0 N L----,C3 \ /
a N N
FIN, J.. 01-CN-CN.. -* - kb G
= 0 1 --C-11\1õ,_-µ 0 r-N \N
, .....- , 0 Nri N 0 N--,.(\-1 WO
..r._ N
f nr\j,) ¨C 0 0 N.....õ..., N

P ...._ ___________ p 0 0 / 0 , 0 , 0 / 0 t N- NtZ N- N /4, _N = 0 .H
(trans) 0 r,...A\IH

H2N N.-0 Ni.,..01 0 .---- H2N
I ----N
N,..........N
4 N c). µ

NGN
__a _NI:rb 0 4 , 1, j_GN.-- -c,N-C\N
N , 0 1.1=-NN
N=i H2N 'i---C 0 N. _Rs N=1 C"----, C?

t ` 0 \ N, N"--- "--( E ,N, N N_k_iN
---- --" 0 ( C) -1\10 ( 0 N

H-,N / \ N
H2N / _____ \
N _________ / c NH - N-----/
----( = __a-0 ..--- e'.7--N
N.__\
N, 0N 0N

r.,.-TI

Fi2N / 'N H
N---7 tõ,\cNH . 0 Date Recue/Date Received 2021-09-09 F (s -, -- =N (R) N-CN---CN 0 H2N- ,-/ \

N H2N /-1 N,,,.,--1, NH

Nz,...../N 0 ------Lo .
p* _ 0, 0, ---- , I F (S) F

o 0 o 0 CS) i N F F
0 N _--/ 0 0- = _..N N o Q õN,N_CN
(R) H2N / \ -N=--/

/C? / N /L1 9 R ) i N
_It' Ft _CIN - '''',/ -0 N, (5) 0 $\"'' N 0 0- el N (s) N
X_INs" 0 H2N PN H2N 0 o ....ci Q
F 0 *NN .0 Ne 0 F

---' =N.,t., N----C. 0 Hi I\ 4 N)' N N---N
..'...µN H2N /
=-/
_____________________________________ -4 ____________________________________ 0 0 (-1 =
'''' \ N 0 / \ 0 ---- -' 'N 0 H2N / \ N H2N ON
N"---=/ HN3 0 0 H

1.
o 0--0....N, (...._ N
--õ, e-- N
' N J 0 / \N
/

H2N \( N-=-=/
NH
N
N=rj 0 Date Recue/Date Received 2021-09-09 N...._LN., --- NH
0jr'j 0 H2N NIN.---"C/ 0 , \ / \ N

N=-/ N.---/
N--,,- \ N.-,- \
112 N 1-11 \ I
\ 7 N \ , N
0 \ N
N"" 0 (traZ1 N,-- F
N.
...,.

N

---1'.

= 0 H 0 = 0 N
0 c,.N1 o N
N

/
\ 1`1 N---CN¨(-- H2N
H
HN N
H
0 N.," \ N 0 0*() NN 3X>

* 0 i 0 ,._ .
:.--j -,--cr.
õ.3 ____ N-,--`, H

Or,. ih 3 iry j 6-C1, H
r; ., H2N)-4N
N\H2N \ ,N 0 0\NI0 0 0 H to___=L
N
_ p-CN--00,1_0 1 N N____) , A Itil.r. 0 ..L') 0 ''s 0 ==,.0 N "-- N -\ , .
a Date Recue/Date Received 2021-09-09 H
0 CL'''''-------0 N,---',N _cv/H t.rrcIt4-0,_;N 0 N----------\ N, N N -= N

H2N / \ N
INJ

P PN
--_/N- N---"-Nu Cr"? H
f-N-11:1VIN N
'---0 ------1`1 --') 0 *N ON---'"i H 0 H
,, ,r4 H2r,i / \ N H7N-(7VA4 N=f rj-/
0 0 __ 0 p .... / N

N C'''Cym..N_Ci Fi2N / \ N Nji 0 ,..---...,f.0 ________________________________ ¨14N-X ________ \IN¨C)CN

0 .
Some embodiments of the present invention relate to a compound represented by general formula (I) or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein the salt is selected from trifluoroacetate.
The present invention relates to a pharmaceutical composition, comprising the compound described in the present invention or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, and a pharmaceutically acceptable carrier.
The present invention relates to the use of the compound described in the present invention or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof in the manufacture of a medicament for treating Date Recue/Date Received 2021-09-09 diseases related to BTK activity or expression level.
The present invention relates to the use of the compound described in the present invention Of a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof in the manufacture of a medicament for treating 5 diseases related to the inhibition or degradation of BTK.
The present invention relates to the use of the compound described in the present invention or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, and the disease is selected from tumors or autoimmune diseases.
10 The present invention relates to the use of the compound described in the present invention or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, the tumor is selected from non-Hodgkin's lymphoma, chronic lymphocytic leukaemia, mantle cell lymphoma, B cell lymphoma, and the autoimmune disease is selected from rheumatoid arthritis or psoriasis.
15 Synthetic method 1:
R1-Cy 1 -Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-R2 B H (Z-2) B-Akl -Cy 1 -Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-R2 (Z-1) (Z-3) (Z-4) B-Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-K
(11) General formula (Z-1) and general formula (Z-2) are subjected to reductive amination, nucleophilic substitution reaction or coupling reaction to obtain the corresponding general formula (Z-3), and if the general formula (Z-3) has an amino 20 protecting group at the reaction site, the amino protecting group is removed first, and then it is subjected to nucleophilic substitution reaction with general formula (Z-4) to obtain the corresponding general formula (II), namely, general formula (I), and the preparation of longer chains can be achieved by repeating the process in the first step above and removing the amino protecting group;
25 R4-Cy1-R5 (Z-2-1) + R6-Cy2-R7 (Z-2-2) -,-R4-Cy1-Ak2-Cy2-R7 (Z-2-3), general formula (Z-2-1) and general formula (Z-2-2) can be subjected to nucleophilic substitution reaction, coupling reaction or reductive amination to obtain Date Recue/Date Received 2021-09-09 general formula (Z-2-3), and the preparation of longer chains can be achieved by repeating the process above;
if (Z-2-1) has an amino protecting group at the reaction site, the protecting group is removed, and then it can be subjected to nucleophilic substitution reaction or coupling reaction or reductive amination with general formula (Z-2-2) to obtain general formula (Z-2-3), and the preparation of longer chains can be achieved by repeating the process above;
or general formula (Z-1) and general formula (Z-2-1) are subjected to nucleophilic substitution reaction, coupling reaction or reductive amination reaction (the chain length can be increased by means of the preparation method for general formula (Z-2-3)) to obtain the corresponding general formula (II), namely, general formula (I), wherein the length of L chain can be prepared by means of the preparation method for general formula (2-2-3).
Synthetic method RI-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-R2 R3-K (Z-2) R1-Cy1 -Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-K
(Z-4) (Z-5) B¨H
(Z-1) B-Aki -Cyl -Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-K
(in If general formula (Z-2) has an amino protecting group at the reaction site, the amino protecting group is removed first, and then it is subjected to nucleophilic substitution reaction or coupling reaction with general formula (Z-4) to obtain the corresponding general formula (Z-5), and general formula (Z-5) and general formula (Z-1) are subjected to nucleophilic substitution reaction or coupling reaction to obtain the corresponding general formula (II), namely, general formula (I).
Synthetic method III:
A part of the chain L can be subjected to nucleophilic substitution reaction or coupling reaction with general formula (Z-1) first, and then subjected to nucleophilic substitution reaction or coupling reaction with other parts of the chain L
(see the preparation of general formula (Z-2-3) for the synthetic method), by such analogy, to obtain general formula (Z-3), and general formula (Z-3) and general formula (Z-4) Date Recue/Date Received 2021-09-09 are subjected to nucleophilic substitution reaction or coupling reaction to obtain the corresponding general formula (II), namely, general formula (I).
Synthetic method IV:
Alternatively, a part of the chain L can be subjected to nucleophilic substitution reaction or coupling reaction with general formula (Z-4) first, and then subjected to nucleophilic substitution reaction or coupling reaction with other parts of the chain L
(see the preparation of general formula (Z-2-3) for the synthetic method), by such analogy, to obtain general formula (Z-5), and general formula (Z-5) and general formula (Z-1) are subjected to nucleophilic substitution reaction or coupling reaction to obtain the corresponding general formula (II), namely, general formula (I).
Synthetic method V:
OH-134-H (Z-7) OH-B4-L-R2 (Z-8) OTs-B4-L-R2 (Z-9) +131-W 1 -B2-B3-H (Z- 10) B-L-le (Z-3) General formula (Z-7) and general formula (Z-2) are subjected to nucleophilic substitution reaction or coupling reaction to obtain general formula (Z-8) or general formula (Z-7) is subjected to nucleophilic substitution reaction or coupling reaction with a part of the chain L, and then is subjected to nucleophilic substitution reaction or coupling reaction with other parts of the chain L
(see the preparation of general formula (Z-2-3) for the synthetic method), to obtain general formula (Z-8), and general formula (Z-8) is reacted with p-toluenesulfonyl chloride to obtain general formula (Z-9), and general formula (Z-9) is subjected to nucleophilic substitution reaction or coupling reaction with general formula (Z-10) to obtain general formula (Z-3).
Synthetic method VI:
R4-cy-i-R5 R6-cy2-R7 (7-2-1) (7-2-2) B H _____________________ r B-Akl-Cyl -R5 _______ B-Ak1-Cy1-Ak2-Cy2-R7 (Z-1) (Z-11) (Z-12) (Z-4) _________________ 1 B-Ak1-Cy1-Ak2-Cy2-Ak3-K
(Z-13) General formula (Z-1) and general formula (Z-2-1) are subjected to reductive Date Recue/Date Received 2021-09-09 amination reaction to obtain the corresponding general formula (Z-11), and if general formula (Z-11) has an amino protecting group at the reaction site, the amino protecting group is removed first, and then it is subjected to reductive amination reaction with general formula (Z-2-2) to obtain general formula (Z-12), and if general formula (Z-12) has an amino protecting group at the reaction site, the amino protecting group is removed first, and then it is subjected to nucleophilic substitution reaction with general formula (Z-4) to obtain general formula (Z-13), namely, general formula (I).
Synthetic method Vii:
HO-B4-R2 Ms0-84-R2 t B1-W1 -B2-133-H w B1-W1-B2-133-B4-R2 (Z-14) (I-15) (Z-10) (2-16) R4-Cy1 -R5 R6-Cy2-R7 (Z-2-1) (Z-2-2) _________________ r- B-Akl -Cy1-R5 w- B-Ak1-Cy1-Ak2-Cy2-R7 (Z-11) (Z-12) (Z-4) ________________ A B-Akl -Cyl -Ak2-Cy2-Ak3-K
(Z-13) General formula (Z-14) is reacted with methanesulfonyl chloride to obtain general formula (Z-15), and general formula (Z-15) and general formula (Z-10) are subjected to nucleophilic substitution reaction to obtain general formula (Z-16), and if general formula (Z-16) has an amino protecting group at the reaction site, the amino protecting group is removed first, and then it is subjected to reductive amination with general formula (Z-2-1) to obtain the corresponding general formula (Z-11), and if general formula (Z-11) has an amino protecting group at the reaction site, the amino protecting group is removed first, and then it is subjected to reductive amination reaction with general formula (Z-2-2) to obtain general formula (Z-12), and if general formula (Z-12) has an amino protecting group at the reaction site, the amino protecting group is removed first, and then it is subjected to nucleophilic substitution reaction with general formula (Z-4) to obtain general formula (Z-13), namely, general formula (1).
See J. Med. Chem. 2015, 58, 9625-9638 for the synthetic method of general Date Recue/Date Received 2021-09-09 formula (Z-1); and see WO 2017197056 for the synthetic method of general formula (Z-4);
R1 is selected from (-0), -CHO, F, Cl, Br, 1, or OTf;
R2 is selected from H, (=0), -CHO, F, Ch Br, 1 or an amino protecting group, preferably Boc;
R3 is selected from NH2, F, Cl, Br, 1, OTf, or OH;
R4, R5, R6 and R7 are each independently selected from H, (=0), -CHO, H, F, Cl, Br, 1, OTf or an amino protecting group.
Unless stated to the contrary, the terms used in both the description and the claims have the following meanings:
The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention all comprises their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention is optionally further substituted by one or more of their corresponding isotopes, wherein the isotopes of carbon comprise 12C, 13C and 14C, the isotopes of hydrogen comprise protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as superheavy hydrogen), the isotopes of oxygen comprise 160, 170 and 180, the isotopes of sulfur comprise 32S, 33S, MS and 36S, the isotopes of nitrogen comprise '4N and 15N, the isotopes of fluorine comprise 17F and 19F, the isotopes of chlorine comprise 'CI and 37C1, and the isotopes of bromine comprise 79Br and 81Br.
"Alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group containing 1 to 20 carbon atoms, preferably alkyl containing 1 to 8 carbon atoms, more preferably alkyl containing 1 to 6 carbon atoms, further preferably alkyl containing I to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isoamyl, neopentyl, n-hexyl and various branched isomers thereof; the alkyl can be optionally further substituted with 0 to 6 substituents selected from F, Cl, Br, I, hydroxyl, sulfhydryl, nitro, cyan , amino, alkylamino, amido, alkenyl, alkynyl, Ci_6 alkyl, C1-6 hydroxyalkyl, C1_6 alkoxy, 3- to 8-membered carbocyclyl, 3- to 8-membered heterocyclic group, 3- to 8-membered carbocyclyloxy, 3- to 8-membered Date Recue/Date Received 2021-09-09 heterocyclyloxy, carboxyl or a carboxylate group, and the definition of the alkyl described herein is consistent with this definition.
"Alkoxy" refers to -0-a1kyl. Non-limiting examples include inethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropoxy and cyclobutoxy. The alkyl can be optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, sulfhydryl, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclic group, carbocyclyloxy, heterocyclyloxy, carboxyl or a carboxylate group. The definition of the alkoxy described herein is consistent with this definition.

"Heterocyclic group" or -heterocyclic ring" refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring, and the aromatic ring or non-aromatic ring can be 3- to 8-membered monocyclic ring, 4-to 12-membered bicyclic ring or 10- to 15-membered tricyclic ring system, and contains 1 to 3 heteroatoms selected from N, 0 or S. preferably 3- to 8-membered heterocyclic 15 group, and the optionally substituted N, S in the heterocyclic group can be oxidized into various oxidation states. Heterocyclic group can be connected to a heteroatom or carbon atom, and heterocyclic group can be connected to a bridged ring or spim ring.
Non-limiting examples include oxiranyl, azacyclopropyl, oxetanyl, azetidinyl, 1,3-dioxolane, 1,4-dioxolane, 1,3-dioxane, azacycloheptyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidyl, piperadinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dih ydropyrany I, dithiolanyl, tetrahydro furanyl, te trahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, azabicyclo[3.2.1loctyl, 25 azabi cyclo [5 .2.0]nonyl, oxatricyclic[5 .3 .1.1]dodecyl, azaadamanty I and oxaspirol3.3Theptyl. The heterocyclic group can be optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, =0, hydroxyl, sulfhydryl, nitro, cyano, amino, alkylamino, ami do, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclic group, carbocyclyloxy, heterocyclyloxy, carboxyl or a carboxylate 30 group.
The definition of the heterocyclic group described herein is consistent with this definition.
Date Recue/Date Received 2021-09-09 "Spiro ring" refers to a 5- to 20-membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between substituted or unsubstituted monocyelic rings, which may contain 0 to 5 double bonds, and may contain 0 to 5 heteroatoms selected from N, 0 or S(=0)1. The Spiro ring is preferably 6- to 14-membered, further preferably 6- to 12-membered, and more preferably 6- to 10-membered. Its non-limiting examples include:
Oa +00 -1-00 4-0> -1-0 1-(3><
1-00 -1-00 I-00) 4-00 '1>c) i-CX> +,O< i3c00 4.45, and . When the spiro ring is substituted, substituents can be I to 5 groups selected from F, Cl, Br, 1, alkyl, cycloalkyl, alkoxy, haloalkyl, mercaptan, hydroxyl, nitro, sulthydryl, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic group, bridged ring group, Spiro ring group, fused ring group, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, formate, -(CH
m -0-(0-12)m-C(=0)-R3, -(C112)m-q=0)-NRbRc, -(CH2)mS(=0).R3, -(C1-12)m-alkenyl-Ra, ORd or -(CH2)m-alkynyl-Ra (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR'Re and the like, wherein Rb and Re are independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, sulfonyl, trifluorornethylsulfonyl. Alternatively, Rb and RC may form a five- or six-membered cycloalkyl or heterocyclic group. R3 and Rd are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic group, carbonyl, ester group, bridged ring group, Spiro ring group or fused ring group.
The definition of the spiro ring described herein is consistent with this definition.
"Fused ring" refers to a polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain 0 or more double bonds, which may be substituted or unsubstituted, and each ring in the fused ring system may contain 0 to 5 heteroatoms selected from N, S(=0), or 0. The fused ring is preferably 5- to 20-membered, further Date Recue/Date Received 2021-09-09 preferably 5- to 14-membered, more preferably 5- to 12-membered, and still further preferably 5- to 10-membered. Non-limiting examples include:
----- -0 _ ' WY.
K, n.CO -VO>
s , ¨s =
NH
, N , H s and When the fused ring is substituted, substituents can be 1 to 5 groups selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, mercaptan, hydroxyl, nitro, sulfhydryl, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic group, bridged ring group, Spiro ring group, fused ring group, hydroxyalkyl, ----0, carbonyl, aldehyde, carboxylic acid, formate, -(Cl12)m-C(=0)-Ra, -0-(C1 12)m-C(=0)-R", -(Cl12)m-C(=0)-NRbRc, -(CH2)mS(=0),R3, -(CH2)m-alkenyl-Ra, ORd or -(CH2)m-alkynyl-Ra (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NRbRc and the like, wherein Rb and RC
are independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, sulfonyl, trifluoromethylsulfonyl.
Alternatively, Rb and RC may form a five- or six-membered cycloalkyl or heterocyclic group. Ra and Rd are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic group, carbonyl, ester group, bridged ring group, Spiro ring group or fused ring group. The definition of the fused ring described herein is consistent with this definition.
"Bridged ring" refers to a polycyclic group containing any two carbon atoms that are not directly connected, which group may contain 0 or more double bonds and can be substituted or unsubstituted, and any ring in the bridged ring system may contain 0 to 5 heteroatoms or groups selected from N, or 0 (wherein n is 0, 1, or 2). The ring atoms contain 5 to 20 atoms, preferably 5 to 14 atoms, further preferably 5 to 12 atoms, and still further preferably 5 to 10 atoms. Non-limiting examples include Date Recue/Date Received 2021-09-09 iN

HN FIN
o.

and adamantane. When the bridged ring is substituted, substituents can be 1 to groups selected from F, Cl, Br, 1, alkyl, cycloalkyl, alkoxy, haloalkyl, mercaptan, hydroxyl, nitro, sulthydryl, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic group, bridged ring group, Spiro ring group, fused ring group, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, formate, -(CH2)m-C(=0)-Ra, -0-(CH2)m-C(=0)-Ra, -(CH2)m-C(-0)-NRbRc, -(CH2),,,S(-0)nR3, -(CH2)m-alkeny1-Ra, 0.1Zd or -(CH2)m-alkynyl-R" (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NRiae and to the like, wherein Rb and R.' are independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, sulfonyl, trffluoromethylsulfonyl. Alternatively, Rh and RC may form a five- or six-membered cycloalkyl or heterocyclic group. Wand Rd are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic group, carbonyl, ester group, bridged ring group, Spiro ring group or fused ring group. The definition of the bridged ring described herein is consistent with this definition.
"Mono-heterocyclic ring" refers to "heterocyclic group" or "heterocyclic ring"

in a monocyclic ring system, and the definition of the mono-heterocyclic ring described herein is consistent with this definition.
"Fused heterocyclic ring" refers to an "fused ring" containing heteroatom(s).
The definition of the fused heterocyclic ring described herein is consistent with this definition.
"Spiro-heterocyclic ring" refers to a "spiro ring" containing heteroatom(s).
The definition of the spiro-heterocyclic ring described herein is consistent with this definition.
Date Recue/Date Received 2021-09-09 "Bridged-heterocyclic ring" refers to a"bridged ring" containing heteroatom(s).
The definition of the bridged-heterocyclic ring described herein is consistent with this definition.
"Heteroaryl" or "heteroaryl ring" refers to a substituted or unsubstituted 5-to 14-membered aromatic ring, and contains I to 5 heteroatoms or groups selected from N, 0 or S(-0)n, preferably 5- to I 0-membered aromatic ring, further preferably 5- to 6-membered. Non-limiting examples of heteroaryl include, but are not limited to pyridyl, furanyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidyl, morpholinyl, thiomorpholinyl, 1,3 -dithianyl, benzimidazolyl, benzimidazole, benzopyridine, pyi-rolopyridine and the like.
The heteroaryl ring can be fused to an aryl, heterocyclic group or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include c__)/ ,20 N.,õ0 N s 0 õ>
NA. NA. /
' N
is and When the heteroaryl ring is substituted, substituents can be 1 to 5 groups selected from F, CI, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, mercaptan, hydroxyl, nitro, sulthydryl, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic group, bridged ring group, Spiro ring group, fused ring group, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, formate, -(CH2),-0-C(-0)-R0, -0-( CH2)m-C(-0)--(CH2) -C(-----0)-NRbRe, -(CH2)1-a1kenyl-R3, ORd or -(CF12)1-m alkynyl-R2 (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NRbRc and the like, wherein Rb and RC are independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, sulfonyl, trifluoromethylsulfonyl. Alternatively, Rb and RC may form a five- or six-membered cycloalkyl or heterocyclic group. R" and Rd are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic group, carbonyl, ester group, bridged ring group, Spiro ring group or fused ring group. The definition of the heteroaryl or heteroaryl ring described herein is consistent with this definition.
Date Recue/Date Received 2021-09-09 "Optional" or "optionally" refers to that the event or circumstance subsequently described may but not necessarily occur, and the description includes the occasions where the events or circumstances occur or do not occur. for example, "Alkyl optionally substituted with F" means that an alkyl may but not necessarily be substituted by F, and the description includes the case where the alkyl is substituted with F and the case where the alkyl is not substituted with F.
"Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof' refers to a salt of the compound of the present invention maintaining the biological effectiveness and characteristics of the free acid or free base, and obtained by reacting 10 the free acid with a non- toxic inorganic base or organic base, reacting the free base with a non- toxic inorganic acid or organic acid.
"Pharmaceutical composition" refers to a mixture of one or more of the compounds of the present invention, a pharmaceutically acceptable salt or a prodrug thereof, and other chemical components, wherein "other chemical components"
refer 15 to pharmaceutically acceptable carriers, excipients and/or one or more other therapeutic agents.
"Carrier" refers to a material that does not cause significant irritation to the organism and does not eliminate the biological activity and characteristics of the administered compound.

"Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate the administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including mierocrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, adhesives and disintegrants.

"Prodrug" refers to a compound that can be converted into a compound of the present invention with biological activity through metabolism in vivo. The prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug 30 of the present invention is administered to a mammalian individual, the prodrug is split to form free amino or carboxyl group.
Date Recue/Date Received 2021-09-09 "Co-crystal" refers to a crystal formed by the combination of active pharmaceutical ingredient (API) and co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds. The pure state of API and CCF are both solid at room temperature, and there is a fixed stoichiometric ratio between various components. The co-crystal is a multi-component crystal, which includes both a binaiy co-crystal formed between two neutral solids and a multi-element co-crystal formed between a neutral solid and a salt or solvate.
"Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and domestic animals, preferably humans, horses, or dogs.
"Stereoisomer" refers to an isomer produced by different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
"Optional" or "optionally" or "selective" or "selectively" refers to that the events or conditions subsequently described may but not necessarily occur, and the description includes the case where the events or conditions occur and do not occur.
For example, "heterocyclic group optionally substituted with alkyl" refers to that the alkyl may but not necessarily exist, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted with alkyl.
"DC50" refers to the dose at which 50% of the protein is degraded.
Detailed Description of Embodiments The technical solutions of the present invention will be described in detail below in conjunction with examples, but the protection scope of the present invention includes but is not limited thereto.
The structures of the compounds are determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (6) is given in the unit of le (ppm). NMR is measured with (Bruker Avance III 400 and Bruker Avance 300) NMR instrument, and the solvent for determination is deuterated dimethyl sulphoxide (DM SO-d6), deuterated chloroform (CDC13), deuterated methanol (CD30D), and the internal standard is tetramethylsilane (TMS);
Date Recue/Date Received 2021-09-09 MS is measured with (Agilent 61 20B(ESI) and Agilent 612011(APCI));
14PLC is measured with Agilent 1260DAD high pressure liquid chromatography (Zorbax SB-C18 100 4.6 mm, 3.5 1.1M);
Yantai Huanghat HSGF254 or Qingdao GF254 silica gel plate is used for thin layer chromatography silica plate, and the silica gel plate for the thin layer chromatography (TLC) is of the specification of 0.15 mm-0.20 mm, and the specification when separating and purifying a product by thin layer chromatography is 0.4 mm - 0.5 mm.
For the column chromatography, Yantai Huanghai silica gel of 200-300 mesh silica gel is generally used as a carrier;
the known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from Titan Technology Co., Ltd., Energy Chemical Co., Ltd., Shanghai Demo Co., Ltd., Chengdu Kelong Chemical Co., Ltd., Accela ChemBio Co., Ltd., J&K Scientific Co., Ltd. and other companies;

[n[iN
0 _ir4=4;1 0 ¨

P131:
(References for synthesis: Y. Sun, X. Zhao, N. Ding, H. Gao, Y. Wu, Y. Yang, M. Zhao, J.
Hwang, Y. Song, W. Liu, Y. Rao, Cell Res. 2018, 28, 779-781);
Tf: Trifluoromethylsulfonyl;
Boc: Tert-butoxycarbonyl;
Ts: P- toluenesulfonyl;
Cbz: Benzyloxycarbonyl;
Ms: Methylsulphonyl;
TMS: Trimethy 1st lane; DM SO: Dimethyl sulphoxide; DMF: N ,N
dimethylformamide; DME: Ethylene glycol dimethyl ether; DCM: Dichloromethane;
DIPEA: N,Nt-diisopropylethylamine; DCE: 1,2-dichloroethane; Pd2dba3:
Tris(dibenzylidene acetone)dipalladium; JohnPhos: (2-biphenyl)di-tert-butylphosphine; THF: Tetrahydrofuran; D1AD: Diisopropyl azodicarboxylate; CD1:
Date Recue/Date Received 2021-09-09 N,N'-carbonyl diimidazole; MsCI: Methanesulfonyl chloride; TFA:
Trifluoroacetic acid.
Example 1:
5424444-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-dipyrimidin-1-ylj-1-piperidy1]-7-azaspiro[3.5]nonan-7-y1]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (compound 1) oo N N ,Thr NH

NN N=NN 1`4N

N¨CNH Stp IN¨CN¨OCN-Boc step 2 \NI I
1 -x=-=

1 a b Ic N
H2N-L\
'44111 0 Step I:
Tert-butyl 24444-amino-3-(4-phenoxyphenyppyrazolo[3,4-d1pyrimidin-1-y11-1-pipericiy1]-7-azaspiro[3.5jn0nane-7-carboxylate (lb) N--="-NN
H2N I __ \N¨OCN¨Boc e 3-(4-phenoxypheny1)-1-(piperidin-4-y1)-1H-pyrazolo[3,4-djpyrimidin-4-amine (la) (see .1. Med. Chem. 2015, 58, 9625-9638 for the synthetic method) (0.200 g, 0.473 mmol) was dissolved in 5 mL of 1,2-dichloroethane, tert-butyl 2-oxo-7-Date Recue/Date Received 2021-09-09 azaspiro[3.5]nonane-7-carboxylate (0.100 g, 0.418 mmol) and glacial acetic acid (0.0567 g, 0.946 mmol) were added, and the mixture was stirred at room temperature for Iii, and then sodium triacetoxyborohydride (0.177 g, 0.836 mmol) was added.
Upon completion of the addition, the reaction was carried out at room temperature overnight. The pH was adjusted to 9-10 by adding dropwise saturated sodium bicarbonate solution. The reaction solution was concentrated under reduced pressure, and then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 100 : 0-9: 1), to obtain tert-butyl 2[444-ami no-3-(4-phenoxyphenyl)pyrazolo [3,4-d]pyrimidin-l-yI]-1-piperidylj-7-azaspiro[3.5]nonane-7-carboxylate (lb) (0.152 g, yield: 60%).
11-1 NMR (400 MHz, DMSO-d6) 6 8.23 (s, 1H), 7.66 (d, 2H), 7.44 (t, 2H), 7.24 -7.05 (in, 511), 4.70 - 4.60 (in, 111), 3.35 -3.25 (m, 4H), 3.22 -3.16 (in, 2H), 2.97 -2.87 (m, 2H), 2.78 - 2.65 (m, 1H), 2.24 -2.11 (m, 2H), 2.03 - 1.94 (m, 2H), 1.94 -1.84 (m, 41-1), 1.60- 1.51 (m, 2H), 1.48 (t, 2H), 1.38 (s, 9H).
LCMS m/z = 610.3 [M+1]+.
Step 2:
1-[1 -(7-Azaspiro [3 .5]nonan-2 -yI)-4-pi peridy1]-3 -(4-phenoxyphenyl)pyrazolo [3 ,4 -d]pylimidin-4 -amine (1c) H2N- N, N--( 'N
Tert-butyl 24444-amino-3-(4-phenoxyphenyppyrazolo[3,4-d]pyrimidin-1-y11-1-piperidyli-7-azaspiro[3.5]nonane-7-carboxylate (lb) (0.150 g, 0.246 mmol) was dissolved in 2 mL of dichloromethane, 5 niL of 4 N ethyl acetate hydrochloride solution was added, and the mixture was stiffed at room temperature for 2 h.
The reaction solution was concentrated under reduced pressure, and then to the residue was added 20 rtiL of dichloromethane. The pH was adjusted to 9-10 with saturated sodium bicarbonate solution. The liquid separation was conducted, and the organic layer was dried over anhydrous sodium sulphate, and concentrated under reduced Date Recue/Date Received 2021-09-09 pressure to obtain I -[1-(7-azaspiro [3 .5]nonan-2-y1)-4-piperidy1}-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine (lc) (0.090 g, yield: 72%).
LCMS tn/z ¨ 510.3 [M-Flr.
Step 3:
5 5-[2-[4-[4-Am ino-3-(4-phenoxyphenyl)pyrazol o[3 ,4-d]pyrim i I -piperidy1]-7-azaspiro[3.5]nonan-7-y1]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (compound 1) NH
HN N

1-[1-(7-azaspiro [3.5] nonan-2-y1)-4-piperidy11-3-(4-io phenoxyphenyl)pyrazolo [3 ,4-d ]pyrimidin-4-am inc (1e) (0.090 g, 0.18 mmol) was dissolved in 2 mL of dimethyl sulphoxide, 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (0.049 g, 0.18 mmol) and diisopropylethylamine (0.11 g, 0.88 mmol) were added. Upon completion of the addition, the reaction was carried out at 90 C for 2 h. The reaction is solution was cooled to room temperature, to which 10 mL of water was slowly added dropwisc, and filtered. The filter cake was dissolved with 20 mL of diehloromethane, and then washed with 5 mL of saturated sodium chloride solution. The liquid separation was conducted, and the organic layer was dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was 20 separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 100 : 0-9 : 1), to obtain 5424444-amino-3-(4-phenoxypheny 1)pyrazolo [3,4-d] pyri midin- -y1]- I -p iperidy I] -7-azasp ro [3 .5]nonan-7-y1]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (compound 1) (0.092 g, 68%).

(400 MHz, CDC13) 6 8.61 (s, 11-1), 8.39 (s, 111), 7.68 - 7.60 (m, 311), 7.39 (t, 2H), 7.27 (d, 1H), 7.20 - 7.06 (in, 3H), 7.09 (d, 2H), 7.04 (dd, 1H), 5.56 (br, Date Recue/Date Received 2021-09-09 211), 4.97 - 4.90 (m, 111), 4.80 (s, 111), 3.38 (dd, 4H), 3.06 (s, 2H), 2.95 -2.66 (m, 511), 2.44 (s, 211), 2.12 (dd, 61-1), 1.69 (d, 611).
LCMS tn/z ¨ 383.8 [M/2 +1].
Example 2:
54444- [4- [4-am ino-3-(4-phenoxyphenyppyrazol o [3,4-d]pyrimid in- 1-y1]-1 -p iperidy11- 1 -piperidyli -1 -p iperid yli-2-(2,6-d ioxo-3-piper idy I )iso indoline- 1 ,3-d ione (compound 2) N'N----ON---Ci 0 1\1 H2 4 N----=/
c 2 (i) N-acc SteT1 2 H,N / NN
1 a 2a 2b r-N-60.9 rr_c-j=NH .

c, i.pl,N,_Cli.'N--GN--\--j .S1r, 4 0 stcp 5 ___________________________________________________________ 7 H2N¨ON H2N4 N
2c al QIS
H2NN (pound 2 N=./
Step 1:
Tert-butyl 4-[4-[4-amino-344-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-y11-1 -piperidy lipiperidine- 1 -carboxy late (2a) Date Recue/Date Received 2021-09-09 Boc N , N
/ H2N \N
N
3-( 4-phenoxypheny1)-1-(piperid in-4-y1)-1H-pyrazo lo [3,4-d]pyrim id in-4-am ine (1a) (see d. Med. Chem. 2015, 58, 9625-9638 for the synthetic method) (0.500 g, 1.29 mmol) was dissolved in 5 mL of 1,2-diehloroethanc, to which was added tert-butyl 4-oxopiperidine- 1 -carboxylate (0.309 g, 1.55 mmol) and glacial acetic acid (0.412 g, 6.86 mmol). Upon completion of the addition, the reaction was stirred at 65 C
for 3 h, then the reaction system was cooled to room temperature, and sodium triacetoxyborohydride (0.548 g, 2.59 mmol) was added. Upon completion of the addition, the reaction was carried out at room temperature overnight. The pH
was adjusted to 9-10 by adding dropwise saturated sodium bicarbonate solution. The reaction solution was concentrated under reduced pressure, and then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) ------ 100 : 0-19: 1), to obtain tert-butyl 44444-amino-3-(4-phenoxyphenyl)pyrazolo[3 ,4-d]pyrimidin-1 -y11-1-piperidy l]piperidine-1 -carboxylate (2a) (0.310 g, yield: 42%).
114 NMR (400 MHz, CDC13) 6 8.34 (s, 1H), 7.64 (d, 2H), 7.39 (t, 2H), 7.19 -7.13 (in, 3H), 7.08 (d, 2H), 5.73 (br, 2H), 4.82 - 4.72 (m, 1H), 4.25 -4.10 (in, 2H), 3.17 - 3.05 (m, 2H), 2.73 (t, 211), 2.60- 2.35 (m, 511), 2.08- 1.99 (m, 211), 1.90- 1.76 (in, 2H), 1.55 - 1.45 (in, 11H).
Step 2:
3-(4-phenoxypheny1)-1-[1-(4-piperi dy1)-4-pi peri dyljpyrazolo [3,4-d]
pyrimidin-4-amine (2b) N
N
H2N \ N
Tert-butyl 4-[4-[4- ami no-3 -(4-phenoxyphenyl)pyrazol o [3,4-d]pyri mi din-l-yll-Date Recue/Date Received 2021-09-09 1-piperidyl]piperidine- 1 -carboxylate (2a) (0.310 g, 0.544 mmol) was dissolved in 2 mL of dichloromethane, 5 mL of 4 N ethyl acetate hydrochloride solution was added, and the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, and then to the residue was added 20 mL
of dichloromethane. The pH was adjusted to 9-10 with saturated sodium bicarbonate solution. The liquid separation was conducted, and the organic layer was dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain phenoxypheny1)-141-(4-piperidy1)-4-piperidyl]pyrazolo[3 ,4-d] pyrimidin-4-amine (2b) (0.256 g, yield: > 99%).
LCMS m/z = 235.8 [M/2+1 r.
Step 3:
Tert-butyl 4441444-arnino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrinaidin-1-y1]-1-piperidyll-1-piperidyl]piperidine-1-earboxylate (2c) N
I-12N --.4=N
/N /N /N¨Boc 3-(4-phenoxypheny1)-1- [1-(4-piperidy1)-4-piperidyl] pyrazolo [3,4-d]
pyrimidin-4-amine (2b) (0.256 g, 0.545 mmol) was dissolved in 3 mL of 1,2-dichloroethane, tert-butyl 4-oxopiperidine- I -carboxylate (0.130 g, 0.654 mmol) and glacial acetic acid (0.174 g, 2.89 mmol) were added. Upon completion of the addition, the reaction was stirred at 65 C for 3 h, and then cooled to room temperature. Sodium triacetoxyborohydride (0.231 g, 1.09 mmol) was added. Upon completion of the addition, the reaction was carried out at room temperature overnight. The p1-1 was adjusted to 9-10 by adding dropwise saturated sodium bicarbonate solution. The reaction solution was concentrated under reduced pressure, and then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) ¨ 100 : 0-19 : 1), to obtain tert-butyl amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimiclin-l-y1]-1-piperidy1]-1-piperidyl]piperidine- 1 -tert-butyl carboxylate (2c) (0.230 g, yield: 65%).
Date Recue/Date Received 2021-09-09 Step 4:
3-(4-phenoxypheny1)-1-[ 1-[ 1-(4-piperidy1)-4-piperidyl] -4-piperidylipyrazolo[3,4-djpyrimidin-4-amine (2d) H2N N., \N \NH
Ten-butyl 4444444-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-y I] -1-piperidy 1]-1 -piperidyl] piperid ine-l-carboxylate (2c) (0.230 g, 0.352 mmol) was dissolved in 2 mL of dichloromethane, 5 mL of 4 N ethyl acetate hydrochloride solution was added, and the mixture was stirred at room temperature for 2 h.
The reaction solution was concentrated under reduced pressure, and then to the residue was added 20 mL of dichloromethane. The p1-1 was adjusted to 9-10 with saturated sodium bicarbonate solution. The liquid separation was conducted, and the organic layer was dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain 3 -(4 -phenoxypheny1)-1 4141- (4-pi peridy1)-4 -piperidy1]-4 piperidyllpyrazolo[3,4-d]pyrimidin-4-amine (2d) (0.195g, yield: >99%).
LCMS m/z = 277.3 [M/2 +1]t Step 5:
54444- [444-amino-344-phenoxypheny Opyrazolo [3 ,4-dipyrini id in - I -yll -1-piperidy1]-I-piperidy111-1-piperidy111-242,6-dioxo-3-piperidyl )isoindoline-I,3-dione (compound 2) o 0 0_ 41 NKN
N=-/
3 -(4-phenoxypheny1)-1- [1-[1-(4-piperidy1)-4-piperidy1]-4-piperidyl]pyrazolo[3,4-djpyrimidin-4-amine (2d) (0.165 g, 0.299 mmol) was dissolved in 2 mL of dimethyl sulphoxide, 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (0.0907 Date Recue/Date Received 2021-09-09 g, 0.328 mmol) and diisopropylethylamine (0.193 g, 1.49 mmol) were added. Upon completion of the addition, the reaction was stirred at 90 C for 2 h. The reaction solution was cooled to room temperature, to which 10 int of water was slowly added dropwise, and filtered. The filter cake was dissolved with 20 mL of dichloromethane, 5 and then washed with 5 mL of saturated sodium chloride solution. The liquid separation was conducted, and the organic layer was dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 100 : 0-92 : 8), to obtain 544444444-amino-3-10 (4-phenoxyphenyppyrazolo[3,4-d]pyrimidin-1-y1]- I -piperidy1]-1-piperidy1]-1-piperidy1]-2-(2,6-dioxo-3-piperidyl)isoindol inc-1,3-dione (compound 2) (0.157 g, yield: 65%).
'H NMR (400 MHz, DMSO-d6) 6 11.06 (s, 1H), 8.23 (s, 1H), 7.67 - 7.64 (m, 31-1), 7.46 -7.40 (m, 2H), 7.31 (s, 1H), 7.25 -7.23 (m, 111), 7.22 -7.10 (m, 5H), 5.06 15 (dd, 1H), 4.67 - 4.57 (m, 1H), 4.10- 4.02 (in, 2H), 3.06- 2.82 (m, 714), 2.62 -2.47 (m, 3H), 2.35 - 2.07 (m, 7H), 2.06 - 1.97 (m, 1H), 1.94 - 1.86 (in, 2H), 1.85 -1.77 (n, 21-1), 1.77 - 1.70 (in, 2H), 1.54 - 1.36 (in, 4H).
LCMS m/z 405.3 [M/2 +1] .
Example 3:
20 54545- [444-amino-3-(4-phenoxyphenyl)pyrazolo [3,4-d]pyrimid in-l-yl] -1-p iperidyl 1pyrimid in -2-y1]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4 -c] pyrrol-2-y1]-2-(2,6-d ioxo -3-p iperidy Disoindol ine-1,3-dione te tratrifl uoroacetate (compound 3) N,'NN
= N frIH
H2N \ I N
õ.\N-C 0 Date Recue/Date Received 2021-09-09 step I o.. Br \- slep 2 N Step N-Boc HO-C\N-C
=N -N
IsO
3a 3b 3c N
N N-CN-C \)-NMN-Boc 4 -NI -N Sic!) 5 ad 3e N NH

N-C\N-C S" 6 N-K \N-E 0 = / J 0 N -N
0 "1111 0 4C F30001-I
3f flo Step 1:
Tert-butyl 2-(5-bromopyrimidin-2-y1)-1,3 ,3 a,4,6,6a-hexahydropyrrolo [3,4-c]pyrrole-5-carboxylate (3b) Br _______________________________________________ (N\)-11--\N-Boc 5-bromo-2-chloro-pyrimidine (1.0 g, 5.17 mmol) was dissolved in 10 triL of anhydrous ethanol, 2-Boc-hexahydropyrrolo[3,4-c]pyrrole (1.32 g, 6.20 mmol) was added, and then triethylamine (1.31 g, 12.9 mmol) was added. Upon completion of the addition, the reaction was stirred at 60 C for 2 h. The reaction solution was cooled to room temperature, and 20 mL of water and 50 mL of ethyl acetate were added.
The liquid separation was conducted, and the organic layer was washed with 20 mL
of saturated sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =
9 : 1-4 : 1), to obtain tert-butyl 2-(5-bromopyrimidin-2-y1)-1,3,3aõ4,6,6a-hexahydropyrrolo[3,4-cipyrrole-5-carboxylate (3b) (1.80 g, yield: 94%).
Step 2:
Tert-butyl 2-[5-(4-hydroxy- 1-piperidyl)primidin-2-y1]-1,3,3a,4,6,6a-hexahydropyrrolo [3,4-c]pyrrole-5-carboxylate (3c) Date Recue/Date Received 2021-09-09 N
HO¨( \N¨E N¨Boc \--"/
Tert-butyl 2-(5-bromopyrimidin-2-y1)-1,3,3 a,4,6,6a-hexahydropyiTolo [3,4-c]pyrrole-5-carboxylate (3b) (1.0 g, 2.71 mmol) was dissolved in 10 mL of dried toluene, 4-hydroxypiperidine (0.548 g, 5.42 mmol), JohnPhos (2-(di-tert-butylphosphine)biphenyl) (0.0808 g, 0.271 mmol, CAS:224311-51-7) and tert-butoxysodium (0.520 g, 5.42 mmol) were successively added. Nitrogen replacement was carried out three times, then Pd2(dba); (0.060 g, 0.135 mmol, CAS:51364-51-3) was added. Upon completion of the addition, the reaction was stirred at 100 C
for 2 h. The reaction solution was cooled to room temperature, and 20 mL of to dichloromethane and 20 mL of water were added. The liquid separation was conducted, and the organic layer was washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4: 1-0: 100), to obtain Is tert- buty I 2-[5-(4-hydroxy-l-piperidyl)pyrimidin-2-y1]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (3c) (0.300 g, yield: 28%).
LCMS m/z = 390.3 [M+1]+.
Step 3:
Tert-butyl 2-[5- [4-(p-tosyl oxy)-1-p iperidyl]pyrimidin-2-y1]-1,3,3a,4,6,6a-20 hexahydropyrrolo [3,4-c]pyrrole-5-carboxylate (3d) N
Ts0¨(\N¨E N N¨Boc / ¨N
Tert-butyl 245-(4-hydroxy-l-piperidyl)pyritnidin-2-y1]-1,3,3a,4,6,6a_-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (3c) (0.300 g, 0.770 mmol) was dissolved in 10 mL of dichloromethane, 4-dimethylaminopyrkline (0.113 g, 0.924 25 mmol) was added, then p-toluenesulfonyl chloride (0.176 g, 0.924 mmol) was added.
Upon completion of the addition, the reaction was carried out at room temperature for 2 h. 20 mL of saturated sodium bicarbonate solution and 20 mL of dichloromethane were added. The liquid separation was conducted, and the organic layer was dried over anhydrous sodium sulphate, and concentrated under reduced Date Recue/Date Received 2021-09-09 pressure, then the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2 : 3-1: 4), to obtain tert-butyl 245- [4-(p- toly lsulfonyloxy)-1-piperidyl]pyrimidin-2-y1]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-cipyrrole-5-carboxylate (3d) (0.420 g, yield: > 99%).
LCMS m/z = 544.3 [M+1 Step 4:
Tert-butyl 2-[5- [4-[4-amino-3-(4-phenoxyphenyl)pyrazolo [3 ,4-d]pyrimidin-1-piperidyl]pyrimidin-2-y1J-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (3e) NN

--Boc / ¨N

Tert-butyl 24544-(p-tosyloxy)-1-piperidyl]pyrimidin-2-y1]-1,3,3a,4,6,6a-hexahydropyrtolo[3,4-c]pyrrole-5-carboxylate (3d) (0.400 g, 0.736 mmol) was dissolved in 5 mL of N,Nr-dimethylforrnamide, and 3-(4-phenoxypheny1)-1-(piperidin-4-y1)-11-1-pyrazolo[3,4-d]pyrimidin-4-amine ( I a) (see J. Med.
Chem. 2015, 58, 9625-9638 for the synthetic method) (0.268 g, 0.883 mmol) was added, and then cesium carbonate (0.479 g, 1.47 mmol) was added. Upon completion of the addition, the reaction was stirred at 80 C for 2 h. The reaction solution was cooled to room temperature, and 10 mL of water and 30 mL of ethyl acetate were added. The liquid separation was conducted, and the organic layer was with washed 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2 : 3-1 : 4) to (dichloromethane/methanol (v/v) = 25 : 2), to obtain tert-butyl 2454444-amino-(4-phenoxyphenyppyrazolo[3,4-dipyrirnidin-l-y1}- -piperidyl]pyrimid 1,3,3a,4,6,6a-hexahydropyrrolo[3,4-cjpyrrole-5-carboxylate (3e) (0.200 g, yield:
40%).
11-1 NMR (400 MHz, CDC13) 8 8.37 (s, 1H), 8.19 (s, 2H), 7.70 - 7.62 (m, 214), Date Recue/Date Received 2021-09-09 7.44 - 7.34 (m, 214), 7.21 - 7.13 (m, 311), 7.13 - 7.05 (m, 2H), 5.80 (br, 2H), 4.94 -4.85 (m, 111), 3.85 - 3.75 (m, 214), 3.72 - 3.58 (m, 214), 3.54-3.46 (m, 411), 3.38 - 3.24 (m, 214), 3.02 - 2.90 (in, 4H), 2.64- 2.52 (m, 211), 2.16 - 2.12 (in, 2H), 1.45 (s, 9H).
LCMS m/z = 675.3 [M+1,1 .
Step 5:
1-[ 14242 ,3,3 a,4,6,6a -hexahydro- I H-pyrrolo[3,4-c]pyrrol- 5-yl)pyrini id in-5-y11-4-piperidy1]-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine (3f) N

-N ¨N
Tert-butyl 2454444-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yli -1-piperidyljpyrimidin-2-y11-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-carboxylate (3e) (0.200 g, 0.296 nimol) was dissolved in 2 mL of dichloromethanc, 10 ifiL o14 N ethyl acetate hydrochloride solution was added, and the mixture was stirred at room temperature for 1 h. The reaction solution was concentrated, and then to the crude product was added 30 mL of dichloromethane. The p14 was adjusted to is 9-10 with saturated sodium bicarbonate solution. The liquid separation was conducted, and the aqueous layer was further extracted with 20 mL of dichloromethane once, the organic layers were combined, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain 1-[1-[2-(2,3,3a,4,6,6a-hexahydro-1H-pyiTolo[3,4-c]pyrrol-5-y1) pyrimidin-5-y1]-4-piperidy1]-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine (30 (0.170 g, yield: > 99%).
LCMS m/z = 288.2 [M/2 Step 6:
54515- [4- [4-amino-3-(4-phcnoxyphenyl)pyrazolo [3,4-dipyrimid in-l-yl] -1-piperidyljpyrimidin-2-y11-1,3,3a,4,6,6a-hexahydropyrrolo [3,4-c] pyrrol-2-y1]-2-(2,6-dioxo-3-piperidypisoindoline-1,3-dione tetratrifluoroacetate (compound 3) Date Recue/Date Received 2021-09-09 NN NH
HN N N N -Tr N-( \N-c 0 ______________________________________ -N 0 1414242,3 ,3a,4,6,6a -hexahydro-1H-pyn-olop ,4-cipyrrol-5-y1) pyri mid in-5-y11-4-piperidy1]-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine (30 (0.170 g, 0.296 mmol) was dissolved in 2 ml.. of dimethyl sulphoxide, and 2-(2,6-5 dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (0.090 g, 0.325 mmol) and diisopropylethylamine (0.191 g, 1.48 mmol) were added. Upon completion of the addition, the reaction was stirred at for 2 h. The reaction solution was cooled to room temperature, to which 10 mL
of water was slowly added dropwise, and filtered. The filter cake was dissolved with 20 10 mL of dichloromethane, then washed with 5 mL of saturated sodium chloride solution.
The liquid separation was conducted, and the organic layer was dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was passed through Pre-HPLC (instrument and preparative column: using (ilison GX-281 to prepare the liquid phase, preparative column model: Sunfire C18, 5 15 inner diameter > length = 30 mm > 150 mm). Preparation method: The crude product was dissolved with methanol and dimethyl sulphoxide, and filtered with 0.45 um filter membrane, to prepare into a sample solution. Mobile phase system:
acetonitrile/water (containing 0.1% TFA). Gradient elution method: gradient elution with acetonitrile from 5% to 60% (elution time: 15 min), the reaction system was 20 lyophilized to obtain 545454444-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrim idin-1 -yl] -1 -p iperi dyl]pyrimidin -2-y1]-1 ,3,3a,4,6,6a-hexahydropyrrol o [3,4-c]pyrrol-2-y1]-2-(2,6-dioxo-3-piperi dyl)i soi ndol ine-1,3-dione tetratrifl uomacetate (compound 3) (0.082 g, yield: 22%).
111 NMR (400 MHz, CDCI3) 6 8.39 (s, 111), 8.36 (s, 111), 8.19 (s, 2H), 7.69 -25 7.59 (m, 3H), 7.40 (t, 211), 7.20 -7.12 (m, 311), 7.11 - 7.06 (m, 2H), 6.96 (d, 111), 6.70 (dd, 111), 6.30 (hw, 2H), 4.95- 4.88 (m, 2H), 3.94- 3.86 (m, 2H), 3.86- 3.70 (m, 2H), 3.60 (dd, 2H), 3.57-3.48 (in, 2H), 3.41 (dd, 211), 3.27-3.12 (in, 2H), 3.04 -2.65 On, Date Recue/Date Received 2021-09-09 611), 2.64-2.51 (m, 211), 2.19-2.10 (m, 2H).
LCMS m/z = 416.3 [M/2 +1].
Example 4:
54245- 14-14-amino-3-(4-phenoxyphenyl)pyrazolo [3,4-d jpyrim id in-1-y11-1 --s piperidyl]pyrimidin-2-y1]-2,7-diazaspiro[3.5jnonan-7-y1]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (compound 4) N,-----:\N
NH
N¨ \N¨eN)¨N( \N --k,o 0 / \ / /
7 N ___________________________________ N

Br--CN / 'NI Sl 2 Slop 3 --ci NleP 1 1 Br---E - s=-.--NCN Bac ep -N -N / -N
3a 4a 4b H2N N I _c _eN
i N N
Ts0 Step 4 -- , /N \ /)-OCN-Boc Step 5 -C\N-C N-NDCN-1:3ac \ N I

4c 4d 0 N.---= N.---'-N
N
Fl2NI C CN N r I --1"0"--- -N

4e Compound 4 a Step 1 lo Tert-butyl 2-(5-bromopyrimidin-2-y1)-2,7-diazaspiro[3.51nonanc-7-carboxylate (4a) Br _____________________________ CNI/)¨N( \N¨Boc N /
Tert-butyl 5-bromo-2-chloro-pyrimidine (3a) (1.0 g, 5.17 mmol) was dissolved in 10 mL of anhydrous ethanol, and 2,7-diazaspiro[3.5]nonane-7-carboxylate 15 hydrochloride (1.60g. 6.20 mmol) was added, and then triethylamine (1.31 g, 12.9 mmol) was added. Upon completion of the addition, the reaction was stirred at for 2 h. The reaction solution was cooled to room temperature, and 20 mL of water and 50 mL of ethyl acetate were added. The liquid separation was conducted, and the organic layer was washed with 30 mL of saturated sodium chloride solution, dried Date Recue/Date Received 2021-09-09 over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ¨ 4 : 1), to obtain tert-buty12-(5-bromopyrimidin-2-y1)-2,7-diazaspiro[3.5[nonane-7-carboxylate (4a) (1.60 g, yield: 81%).
LCMS m/z = 383.1 [M-F-1]-1.
Step 2:
Tert-butyl 2 -[5-(4-hydroxy-l-piperidyl)pyrimidin-2-yl] -2,7-diazaspiro[3.5]nonanc-7-carboxylate (4b) N
N¨Boc /
Tert-butyl 2-(5-bromopyrimid in-2 -y I)-2,7-dia.zaspi ro [3 . 5] nonane -7-carboxy late (4a) (1.00 g, 2.61 mmol) was dissolved in 10 mL of dried toluene, and 4-hydroxypiperidine (0.264 g, 2.61 mmol), JohnPhos (0.0389 g, 0.130 mmol) and tert-butoxysodium (0.251 g, 2.61 mmol) were added. Nitrogen replacement was carried out three times, then Pc12(dba)3 (0.060 g, 0.13 mmol) was added. Upon completion of the addition, the reaction was stirred at 100 C for 2 h. The reaction solution was cooled to room temperature, and 20 mL of dichloromethane and 20 mL of water were added. The liquid separation was conducted, and the organic layer was washed with 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =
4 : 1-0 : 100), to obtain tert-butyl 245-(4-hydroxy- 1 -piperidyl)pyrimidin-2-y1]-2,7-diazaspiro[3.5]nonane-7-carboxylate (4b) (0.530 g, yield: 50%).
'H NMR (400 MHz, DMSO-d6) 6 8.14 (s, 2H), 4.64 (s, 1H), 3.68 (s, 4H), 3.61 -3.53 (m, 1H), 3.31 -3.23 (m, 6H), 2.76 -2.65 (m, 2H), 1.87 - 1.75 (m, 2H), 1.71 -1.59 (m, 4H), 1.58 - 1.44 (m, 2H), 1.39 (s, 9H).
LCMS ni/z = 404.3 [M-i- I]'.
Step 3:
Tert-butyl 2-[5-[4-(p-tosyloxy)-1-piperidyl[pyrimidin-2-y1]-2,7-diazaspiro[3.5]nonane-7-carboxylate (4c) Date Recue/Date Received 2021-09-09 N
\N¨C µ>--N N¨Boc Tert-butyl 2-[5-(4-hydroxy-1-piperidyppyrimidin-2-y1]-2,7-diazaspiro [3 .5]nonane-7- carboxylate (4b) (0.530 g, 1.31 mmol) was dissolved in 10 mL of dichloromethane, and 4-dimethylaminopyridine (0.321 g, 2.63 mmol) was added, then p-toluenesulfonyl chloride (0.501 g, 2.63 mmol) was added. Upon completion of the addition, the reaction was carried out at room temperature for 2 h.
20 mL of saturated sodium bicarbonate solution and 20 mL of dichloromethane were added. The liquid separation was conducted, and the organic layer was dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude to product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2 : 3-1 : 4), to obtain tert-butyl 24544-(p-tosy1oxy)-1-piperidyllpyrimidin-2-y1]-2,7-diazaspiro[3.5]nonane-7-carboxylate (4c) (0.550 g, yield: 75%).
LCMS m/z = 558.3 [M+1] .
Step 4:
Tert-butyl 2454444-amino-3-(4-phenoxyphenyl)pyrazolo [3 ,4-d]pyrimid in-1-ylj -1-piperidyljpyrimidin-2-y1]-2,7-diazaspiro[3.5]nonane-7-carboxylate (4d) I.12N _N
/N1¨( N¨Boc Tert-butyl 2-[5-[4-(p-tosyloxy)-1-piperidyl]pyrim id in-2-yI]-2,7-diazaspiro[3.5jnonane-7-carboxylate (4c) (0.500 g, 0.897 mmol) was dissolved in 5 mL of N.I\l'-dimethylfortnamide, and 3-(4-phenoxypheny1)-1-(piperidin-4-y1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (I a) (see J. Med. Chem. 2015, 58, 9625-9638 for the synthetic method) (0.326 g, 1.08 mmol) was added, and then cesium carbonate (0.584 g, 1.79 mmol) was added. Upon completion of the addition, the reaction was stirred at 80 C for 2 h. The reaction solution was cooled to room temperature, and 10 mL of water and 30 mL of ethyl acetate were added. The liquid separation was conducted, and the organic layer was with washed 10 mL of saturated sodium Date Recue/Date Received 2021-09-09 chloride solution, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ¨ 2 : 3-1 : 4) to (dichloromethane/methanol (v/v) = 25 : 2), to obtain tert-butyl 2454444-amino-(4-ph enoxyph enyl)pyrazolo [3,4-d] pyri m id i n-1-y11- 1-p ip eridyl]pyrimidin-2-y11-2,7-d iazaspiro[3.5]nonane-7-carboxylate (4d) (0.230 g, yield: 37%).
LCMS m/z = 345.3 [M/2 +1r.
Step 5:
1-[1-[2-(2,7-diazaspiro [3.51nonan-2-yl)pyrimidin-5-y11-4-piperidy11-3-(4-phenoxyphenyl )pyrazolo [3,4-d]pyrimi din-4-am inc (4e) H2N _N
NH
/
41111 o Tert-butyl 2 -[5- [4- [4-amino-3 -(4-phenoxyphenyl)pyrazolo [3,4-d]pyrim idin-y11-1-piperidyl] pyrim id in-2-y11-2,7-d iazaspiro [3 .5]nonane-7-carboxy late (4d) (0.230 g, 0.334 mmol) was dissolved in 2 mL of dichloromethane, and 10 mL of 4 N
ethyl Is acetate hydrochloride solution was added, and the mixture was stirred at room temperature for 1 h. The reaction solution was concentrated, and then to the crude product was added 30 mL of dichloromethane. The pH was adjusted to 9-10 with saturated sodium bicarbonate solution. The liquid separation was conducted, and the aqueous layer was further extracted with 20 mL of dichloromethane once, the organic layers were combined, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain 14142-(2,7-diazaspiro[3.5]nonan-2-y1) pyrimidin-5-y11-4-piperidy11-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine (4c) (0.197 g, yield: > 99%).
LCMS m/z = 589.3 [M-F-1]-1'.
Step 6:
5-[2-[5- [4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-dipyrimidin-l-y1]-1-piperidyl]pyrimidin-2-y11-2,7-diazaspiro[3.5]nonan-7-y11-2-(2,6-dioxo-3-piperidyl)isoindolinc-1,3-dione (compound 4) Date Recue/Date Received 2021-09-09 NH
H2N" N
N¨(o 0 14 I 42-(2,7-d iazaspi ro [3 .51nonan-2-y1) pyrimidin-5-y11-4-piperidy11-3-(4-phenoxyphenyppyrazolo[3,4-d]pyrimidin-4-amine (4e) (0.170 g, 0.289 minol) was dissolved in 2 mL of ditnethyl sulphoxide, and 2-(2,6-dioxopiperidin-3-yI)-5-s fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (0.0877 g, 0.318 mmol) and diisopropylethylamine (0.187 g, 1.44 mmol) were added. Upon completion of the addition, the reaction was stirred at 90 C for 2 h. The reaction solution was cooled to room temperature, to which 10 mL of water was slowly added dropwise, and filtered. The filter cake was dissolved with 20 mL of dichloromethane, 10 and then washed with 5 mL of saturated sodium chloride solution. The liquid separation was conducted, and the organic layer was dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichlorotnethane/methanol (v/v) = 100 : 0-92 : 8), to obtain 5-[2-[5-[4-[4-amino-3-15 (4-phenoxyphenyl)pyrazolo [3,4-d]pyrimidin-l-y1}- 1-piperidyllpyrimi din-2-y1]-2,7-diazaspiro [3 .5]nonan-7-y1]-2-(2,6-dioxo-3-piperidypisoindol ine-1,3-dione (compound 4) (0.030 g, yield: 11%).
1H NMR (400 MHz, DM SO-d6) 6 11.06 (s, 1H), 8.28 (s, 1H), 8.25 (s, 2H), 7.68 - 7.65 (m, 3H), 7.44 (t, 2H), 7.35 (s, 1H), 7.28 (d, IFI), 7.22 - 7.09 (m, 5H), 5.06 (dd, 20 1H), 4.90 - 4.80 (in, 1H), 3.77 (s, 4H), 3.63 - 3.58 (m, 2H), 3.55 -3.47 (m, 4H), 2.95 -2.85 (m, 3H),2.63 -2.51 (m, 21-1), 2.40 - 2.27 (m, 2H), 2.05 - 1.97 (m, 311), 1.83 (s, 41-1).
LCMS m/z = 423.3 1M/2 +11.
Example 5:
25 5- [7-[5- [4- [4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-l-y1]-piperidylipyrimidin-2-y11-2,7-diazaspiro[3.5]nonan-2-y1]-2-(2,6-dioxo-3-piperidypisoindoline-1,3-dione (compound 5) Date Recue/Date Received 2021-09-09 NH

= 0 N

N Sicp I Stet, 2 Br---CNN)-- CI Br---0-00J¨Boc HU¨CN--NOC,N"--130C S." __ 3 b ¨N ¨N
3a 5a 5b ¨N

0 ¨ \NN_BOC Step " ,>¨NOCN¨Roc Step ¨N
5c sNN
N NH _____________ N \)¨N N \ 0 0 N ¨N

So ( impound 5 Step 1:
Tert-butyl 7-(5-bromopyrimidin-2-y1)-2,7-diazaspiro[3.51nonane-2-carboxylate (5a) N
'Bac Tert-butyl 5-bromo-2-chloro-pyrimidine (3a) (1.0 g, 5.17 mmol) was dissolved in 10 ml, of anhydrous ethanol, and 2,7-diazaspiro[3.51nonane-2-earboxylate hydrochloride (1.60 g, 6.20 mmol) was added, then triethylamine (1.31 g, 12.9 mmol) was added. Upon completion of the addition, the reaction was stirred at 60 C
for 2 h.
The reaction solution was cooled to room temperature, and 20 mL of water and mL of ethyl acetate were added. The liquid separation was conducted, and the organic layer was washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude is product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ¨ 4 : 1), to obtain tert-butyl 7-(5-bromopyrimidin-2-y1)-2,7-Date Recue/Date Received 2021-09-09 diazaspiro[3.5]nonane-2-carboxylate (5a) (1.60 g, yield: 81%).
Step 2:
Tert-butyl 745-(4-hydroxy-1-piperidyl)pyrimidin-2-yll -2,7-diazaspiro[3.5 jnonane-2-carboxylate (5b) HOX \N¨CN\ ¨N/ _______________________________ nN-Boc ¨N
Tert-butyl 7-(5-bromopyrimidin-2 -yI)-2,7-diazaspiro[3 .5]nonane-2 -carboxylate (5a) (0.500 g, 1.30 mmol) was dissolved in 10 ml, of dried toluene, and 4-hydroxypiperidine (0.264 g, 2.61 mmol), JohnPhos (0.0389 g, 0.130 mmol) and tert-butoxysodium (0.251 g, 2.61 mmol) were added. Nitrogen replacement was carried to out three times, and then Pd2(dba)3 (0.060 g, 0.065 mmo1) was added.
Upon completion of the addition, the reaction was stirred at 100 C for 2 h. The reaction solution was cooled to room temperature, and 20 mL of dichloromethane and 20 mL
of water were added. The liquid separation was conducted, and the organic layer was washed with 10 mL of saturated sodium chloride solution, dried over anhydrous 15 sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4 : 1-0 : 100), to obtain tert-butyl 7-[5-(4-hydroxy- 1 -piperidyl)pyrimidin-2-y1]-2,7-diazaspiro[3.5]nonane-2-carboxylate (5b) (0.200 g, yield: 38%).
20 LCMS m/z = 404.3 [M 1]+.
Step 3:
Tert-butyl 74544-(p-tosyloxy)-1-piperidylipyrimidin-2-y11-2,7-diazaspiro[3.5]nonane-2-carboxylate (Sc) N
Ts0¨( \N¨C \)¨N )<N¨Boe ¨N
25 Tert-butyl 7-[5-(4-hydroxy-l-piperidyppyrimidin-2-y1]-2,7-diazaspiro[3.5jn0nane-2-carboxylate (5b) (0.380 g, 0.942 mrnol) was dissolved in 10 inL of dichloromethane, and 4-dimethylaminopyridine (0.230 g, 1.88 annol) was added, then p-toluenesulfonyl chloride (0.359 g, 1.88 mmol) was added. Upon completion of the addition, the reaction was carried out at room temperature for 2 h.
Date Recue/Date Received 2021-09-09 20 mL of saturated sodium bicarbonate solution and 20 mL of dichloromethane were added. The liquid separation was conducted, and the organic layer was dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2 : 3-1 : 4), to obtain tert-butyl 74544-(p-tosyloxy)-1-piperidyllpyrimidin-2-y11-2,7-diazaspiro[3.5]nonanc-2-carboxylate (5c) (0.440 g, yield: 84%).
LCMS m/z = 558.3 [M+1] .
Step 4:
Tert-butyl 7-[5- [4-[4-amino-3-(4-phenoxyphenyl)pyrazolo [3 ,4-d]pyrimid in-1-y11-1-pi peridyli pyrim id in-2-y1]-2,7-d iazaspiro [3 .5inonane-2-carboxylate (5d) N
H2N N 1 \
N \ KN¨Boc / rt 4111 o Tert-butyl 7-[5-[4-(p-tosyloxy)-1-piperidyl]pyrimidin-2-y1]-2,7-diazaspiro[3.5]nonane-2-carboxylate (Sc) (0.440 g, 0.789 mmol) was dissolved in 5 is mL of N,N'-dimethylformamide, and 3-(4-phenoxypheny1)-1-(piperidin-4-y1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (la) (see J. Med. Chem. 2015, 58, 9625-9638 for the synthetic method) (0.287 g, 0.947 mmol) was added, then cesium carbonate (0.514 g, 1.58 mmol) was added. Upon completion of the addition, the reaction was stirred at 80 C for 2 h. The reaction solution was cooled to room temperature, and 10 mL of water and 30 mL of ethyl acetate were added. The liquid separation was conducted, and the organic layer was with washed 10 mL of saturated sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2 : 3-1 : 4) to (dichloromethane/methanol (v/v) ¨ 25 : 2), to obtain tert-butyl 7454444-amino-(4-phenoxyphenyppyrazolo[3,4-d]pyrimidin-l-ylj-1-piperidyl]pyrimidin-2-y1]-2,7-diazaspiro[3.5]nonane-2-carboxylate (5d) (0.230 g, yield: 42%).
LCMS m/z = 689.3 [M+1]+.
Date Recue/Date Received 2021-09-09 Step 5:
1-[ I -[2-(2,7-diazaspiro [3 . 5]nonan-7-yl)pyrimidin-5-y1]-4-piperidyI]-3-(4-phenoxypheny Opyrazolo [3,4 -d]pyrimidin-4-am ine (Sc) N
H2N 1111 N _N __ NN-( _____________________________________ N-C\ /)-N __ KNH
N

Tert-butyl 7-[54444-amino-3 -(4-phenoxyphenyl)pyrazolo [3 ,4-d]pyrimidin-1-yli -1-piperidyljpyrim idin-2 -y11-2, 7-diazaspiro [3 .5]nonane-2 -carboxylate (5d) (0.230 g, 0.334 mmol) was dissolved in 2 mL of dichloromethane, and 10 mL of 4 N
ethyl acetate hydrochloride solution was added, and the mixture was stirred at room temperature for I h. The reaction solution was concentrated, and then to the crude product was added 30 mL of dichloromethane. The p1-1 was adjusted to 9-10 with saturated sodium bicarbonate solution. The liquid separation was conducted, and the aqueous layer was further extracted with 20 mL of dichloromethane once, the organic layers were combined, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain 14142-(2,7-diazaspiro[3.51nonan-7-y1) pyrimidin-5-yli-4-piperidyli-3-(4-phenoxyphenyl)pyrazolo[3,4-dipyrimidin-4-amine (5e) (0.197 g, yield: > 99%).
LCMS m/z = 589.3 [M+1]+.
Step 6:
54745- [444-amino-3 -(4-phenoxyphenyl)pyrazo lo [3 ,4-d]pyrim id in- I -y1]-1 -20 piperidyljpyrimidin-2-y11-2,7-diazaspiro[3.5]nonan-2-y1]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (compound 5) NN _________________________________________________ 0 NH
_N __________________________________________ N¨K _______________________________ \N-C /)¨NDCN 0 1 41-[2-(2,7-diazaspiro[3.5]nonan-7-y1) pyrimidin-5-yl] -4-piperidy11-3 -(4-phenoxyphenyl)pyrazolo [3,4-d]pyrimid in-4-amine (5e) (0.170 g, 0.289 mmol) was dissolved in 2 mL of dimethyl sulphoxide, and 242,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (0.0877 Date Recue/Date Received 2021-09-09 g, 0.318 mmol) and diisopropylethylamine (0.187 g, 1.44 mmol) were added. Upon completion of the addition, the reaction was stirred at 90 C for 2 h. The reaction solution was cooled to room temperature, to which 10 mL of water was slowly added dropwise, and filtered. The filter cake was dissolved with 20 mL of dichloromethane, and then washed with 5 mL of saturated sodium chloride solution. The liquid separation was conducted, and the organic layer was dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 100 : 0-92 : 8), to obtain 547454444-amino-3-(4-phenoxyphenyppyrazolo[3,4-d]pyrimidin-l-ylj- I -piperidyl]pyrimidin-2-y1]-2,7-diazaspiro[3.5]nonan-2-y1]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (compound 5) (0.040 g, yield: 16%).
'H NMR (400 MHz, CDC13) 6 9.19 (s, 1H), 8.39 (s, 1H), 8.18 (s, 2H), 7.65 (d, 3H), 7.39 (t, 2H), 7.22-7.12 (in, 3H), 7.08 (d, 2H), 6.81 (s, 1H), 6.54 (d, 1H), 5.93 (hr.
2H), 5.00 -4.84 (m, 2H), 3.80 (d, 8H), 3.55 (d, 2H), 3.04-2.66 (in, 5H), 2.66-2.50 (m, 211), 2.20-2.05 (m, 3H), 1.89 (s, 4H).
LCMS in/z = 423.3 [M/2 +1]+.
Example 6:
5 -(3 -(44(4-(4-amino-3 -(4-phenoxypheny1)- 1H-pyrazolo [3 ,4-d]pyrimidin-1-yl)piperidin-l-yl)methyl)piperidin-l-ypazetidin-1-y1)-2-(2,6-dioxopiperidin-3-y1)iso indol in e-1,3 -dione tritrifluoroacetate (compound 6) Atha_ 0 N¨N 3CF3C001-1 ( 0 NH

Date Recue/Date Received 2021-09-09 FI,N1 S
I Ori,c4'NycN:,) O1 = Slep2 II
Mcp 3 N- N
N-N _________________________________ NH LI) \¨CNBoc N\--CNH
6c NNeQc la o to tiTcr 4 S,Ly Bd /¨\\*iNI-0114 Cumputind 6 Step I:
Tert-butyl 4-((4-(4-ami no-3 -(4-phenoxypheny1)-1H-pyrazol o [3 ,4-d]pyrim id in-1-y1) ethyl)pi peridine-l-carboxylate (6a) N¨N
N ( NBoc 3 -(4-phenoxypheny1)-1-(piperidin-4 -y1)-1H-pyrazol o [3 ,4-d] pyrimidin-4 -amine (1 a) (see]. Med. Chem. 2015, 58, 9625-9638 for the synthetic method) (0.25 g, (159 mmol) was dissolved in 20 mL of dichlorornethane, and glacial acetic acid (0.052 g, 0.89 mmol) and tert-butyl 4-formylpiperidine- 1 -carboxylate (0.152 g, 0.71 mmol) were successively added. The mixture was stirred under nitrogen atmosphere for 1 h, sodium triacetoxyborohydride (0.627 g, 2.96 mmol) was added, and the mixture was stin-ed at room temperature overnight. The reaction was quenched by adding 20 mL
of saturated sodium bicarbonate solution, stirred, and allowed to stand for layer separation. The aqueous phase was extracted with dichloromethane (15 mL x 2), and the organic phase was combined, washed with 30 mL of saturated saline, dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure.
The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 100 : 1-25 : 1), to obtain tert-butyl 4-((4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin- I -yl)piperidin-1 Date Recue/Date Received 2021-09-09 yl)methyl)piperidine-l-carboxylate (6a) (0.284 g, yield: 82%).
Step 2:
3-(4-Phenoxypheny1)-1-(1-(pi peridin-4-ylin ethyl)piperidin-4-y1)-1H-pyrazo lo 13,4-d pyri midin-4-am ine (6b) u2N
NN
-N
\ I
J\NH
Tert-butyl 4 -((4-(4-ami no-3 -(4-phenoxyph eny1)-1H -pyrazo lo [3 ,4 -d]pyrimidin-1-yl)piperidin-l-yl)methyl)piperidine-l-carboxylate (6a) (0.284g. 0.487 mmol) was dissolved with 2 mL of methanol, and 10 mL of saturated ethyl acetate hydrochloride solution was added dropwise, and the mixture was reacted at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain a crude product, and the p1-1 of the crude product was adjusted to 8-9 with saturated sodium bicarbonate solution, and the resulted solution was extracted with dichloromethane (20 mL x 3). The organic phase was combined, dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to obtain 3-(4-phenoxypheny1)-1-(1-(piperidin-4-ylmethyl)piperidin-4-y1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (6b) (0.22 g, yield: 94%).
Step 3:
Tert-butyl 3 -(4-((4-(4-amino-3 -(4-ph enoxyphen y1)-1H-pyrazolo[3 ,4-d]pyrimidin-1-y1) piperidin- 1 -yl)methyl)piperidin-l-y1)azetidine-1-carboxylate (6c) u2N
--N
N¨N
( N----CNBoc 3-(4-phenoxypheny1)-1-(1-(piperidin-4-ylmethyl)piperidin-4-y1)-1H-pytazolo[3,4-djpyrimidin-4-amine (6b) (0.22 g, 0.455 mmol) was dissolved in 20 nth of 1,2-dichloroethane, and glacial acetic acid (0.055 g, 0.910 mmol) and ter-t-butyl 3-oxoazetidine- 1 -carboxylate (0.094 g, 0.546 mmol) were successively added.
The mixture was stirred under nitrogen atmosphere for 1 h, sodium triacetoxyborohydride Date Recue/Date Received 2021-09-09 (0.578 g, 2.73 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction was quenched by adding 20 mL of saturated sodium bicarbonate solution, stirred, and allowed to stand for layer separation. The aqueous phase was extracted with dichloromethane (15 mL x 2), and the organic phase was combined, washed with 30 mL of saturated saline, dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 100 : 1-25 : 1), to obtain tert-butyl 3444(444-amino-3-(4-phenoxypheny1)-111-pyrazolo [3,4-d]pyrim 1-(6c) (0.25 g, yield: 86%).
Step 4:
1-( 1-(( 1-(azetidin-3-yppiperidin-4-yOrnethyl)piperidin-4-y1)-3 -(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (6d) V
( Tert-butyl 3 -(44(4-(4-anaino-3 -(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-1 -yl)piperidin-l-yl)methyl)piperid in-l-yl)azetidine-1-carboxylate (6c) (0.25 g, 0.391 mmol) was dissolved with 2 mL of methanol, and 10 mL of saturated ethyl acetate hydrochloride solution was added dropwise, the mixture was reacted at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain a crude product, and the pH of the crude product was adjusted to

8-9 with saturated sodium bicarbonate solution, which was extracted with dichloromethane (20 mL x 3). The organic phase was combined, dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to obtain 1 -( 1-(( 1-(azeti din-3-yl)piperidin-4-y 1)m ethyl)piperidin-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (6d) (0.137 g, yield: 65%).
Step 5:
5-(3-(4-((4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-d]pyrim 1din-1 -yl)piperidin-l-yl)methyl)piperidin-l-yl)azetidin-l-y1)-2-(2,6-dioxopiperidin-3-Date Recue/Date Received 2021-09-09 yl)isoindoline-1,3-dione tritrifluoroacetate (compound 6) H2N _N

¨N

3CFaCOOH
NH
o z 0 1 1-(( 1-(azetidin-3-yl)piperidin-4-yl)methyl)piperidin-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (6d) (0.137 g, 0.254 mmol) was dissolved in 10 mL of dimethyl sulphoxide, and N,N'-diisopropylethylamine (0.330 g, 2.54 mmol) and 2-(2,6-dioxopiperidin-3-yI)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (0.1 g, 0.331 mmol) were successively added, the mixture was heated to 90 C and reacted for 6 h under nitrogen atmosphere. To the reaction solution was added 10 mL of water, a solid was precipitated out, filtered off with suction, and the filtrate was extracted with ethyl acetate (40 mL x 2). The organic phase was combined, washed with 50 mL of saturated saline, dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography (dichloronaethane/methanol (v/v) = 100 : 1-20 : 1), to obtain 0.127 g of a crude product, and the crude product was passed through Pre-IIPLC
(instrument and preparative column: using Glison GX-281 to prepare the liquid phase, preparative column model: Stinfire C18, 5 p.m, inner diameter x length = 30 mmx 150 mm), Preparation method: The crude product was dissolved with methanol and dimethyl sulphoxide, and filtered with 0.45 pm filter membrane, to prepare into a sample solution. Mobile phase system: acetonitrile/water (containing 0.1%
TFA).
Gradient elution method: gradient elution with acetonitrile from 5% to 60%
(elution time: 15 min), the reaction system was lyophilized to obtain 5-(3-(4-((4-(4-amino-3-(4-ph enoxyph eny1)-1H-pyrazolo[3,4-djpyri m idin- I -3/1)piperi d in- 1-ypinethyppiperidin-l-y1)azetid in-l-y1)-2-(2,6-dioxopiperidin-3 -yl )isoindoline-1,3 dione tritrifluoroacetate (compound 6) (78 mg, yield: 27%).
1H NMR (400 MHz, DMSO-d6) 6 11.07 (s, 1H), 8.34 (s, 1H), 7.77-7.62 (m, 3H), Date Recue/Date Received 2021-09-09 7.50-7.41 (m, 214), 7.24-7.10 (m, 511), 6.90 (d, 114), 6.76 (dd, 1H), 5.08 (dd, 211), 4.35 (d, 614), 4.27 (d, 61-1), 3.73 (d, 21-1), 3.62-3.49 (m, 214), 2.97-2.80 (m, 3H), 2.57 (dd, 311), 2.26-1.99 (m, 6H).
LCMS m/z = 398.3 [M/2 +11-.
Example 7:
5-(2-(54(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-1-y1)piperidin- 1 -yl)methyl )pyrimidi n-2-y1)-2,7-diazaspiro [3.5jnonan-7-y1)-2-(2,6-dioxopiperi din-3-ypisoindoline- 1,3 - dione tritrifluoroacetate (compound 7) H2N N, 0 ,(1H
-- I

, 0 NN
fr\iµr M

0 ctH 0 c-tH

Siep I 0 Slep2 0 -N

--- 0 c7CiN
F
Boc--NHN
7a 7b ep I

H2N , -1 N
N
Step 3 0 I
N
1a 7c H2N N 0 O'H

fr\YN
Compound 7 Step I:
Tert-butyl 7-[2-(2,6-dioxo-3-piperidy1)-1,3-dioxo-isoindolin-5 -y1]-2,7-diazaspiro[3.5 ]nonane-2-carboxylate (7a) Date Recue/Date Received 2021-09-09 0 zcfNH
N-Boc-N
2-(2,6-d ioxop iperidin-3-y1)-5-fluoro iso indol ine-1,3-d lone (see WO
2017197056 for the synthetic method) (1.0 g, 3.62 mmol) was dissolved in 20 mL
of DMSO, and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (0.82 g, 3.62 mmol) and DIPEA (N,N-diisopropylethylamine) (2.3 g, 3.62 mmol) were added at room temperature, the reaction was stirred at 90 C for 2 h. To the reaction solution was added 50 rnL of water, the aqueous phase was extracted with ethyl acetate (50 mL x 3), and the organic phase was combined, washed with water (20 mL x 2), dried over anhydrous sodium sulphate, and concentrated. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) =
100: 1-20: 1), to obtain tert-butyl 742-(2,6-dioxo-3-piperidy1)-1,3-dioxo-isoindolin-5-y1]-2,7-diazaspiro[3.5]nonanc-2-carboxylate (7a) (1.0 g, yield: 57%).
LCMS m/z = 483.3 [M 1]'.
Step 2:
5-(2,7-diazaspiro [3. 5]nonan-7-y1)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione hydrochloride (7b) _fp 0 c NH
NCI

HN
Tert-butyl 7-[2-(2,6-di oxo-3-piperidy1)-1,3-dioxo-isoindol in-5 -y1]-2,7-diazaspiro[3.5]nonane-2-carboxylate (7a) (2.0 g, 4.14 mmol) was dissolved in 20 mL
of 4 N ethyl acetate hydrochloride solution, and 5 mL of methanol was added, and the reaction was carried out at room temperature for 2 h. The reaction solution was directly concentrated, to obtain 5-(2,7-diazaspiro[3.5]nonan-7-y1)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione hydrochloride (7b) (1.5 g, yield: 86%).
LCMS m/z = 383.2 [M-Flr.
Date Recue/Date Received 2021-09-09 Step 3:
1-[14(2-chloropyrimidin-5-yl)methyll-4-piperidy11-3-(4-phenoxypheny1)pyrazolo [3,4 -d]pyrimidin-4-am inc (7c) N
ONN NCI
y 3-(4-phenoxypheny1)-1-(piperidin-4-y1)-1H-pyrazolo[3,4-djpyrimidin-4-amine (la) (see Med. Chem. 2015, 58, 9625-9638 for the synthetic method) (2.97 g, 7.0 mmol) was dissolved in 20 mL of I ,2-diehloroethane. At room temperature, 2-chloropyrimidine-5-forrnaldehyde (1.0 g, 7.0 mmol) was added, then I rriI of acetic acid was added, and the mixture was reacted at room temperature for 1 h. To the reaction solution was added sodium triacetoxyborohydride (4.5 g, 21.0 mmol), and the mixture was reacted at room temperature overnight. The reaction solution was poured into 50 mL of saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate (50 mL x 3), and the organic phase was combined, washed with water (50 mL x 2), dried over anhydrous sodium sulphate, and Is concentrated, to obtain 141-[(2-chloropyrimidin-5-y1) methy1]-4-piperidy1]-3-(4-phenoxyphenyppyrazolo[3,4-djpyrimidin-4-amine (7c) (0.4 g, yield: 11.1%).
LCMS m/z = 513.6 [114+1]+.
Step 4:
54245- [[444-amino-3-(4-phenoxyphen yl)pyrazolo[3,4-d] pyrimidin- I -y11]-1 -piperidylimethylipyrimidin-2-y1]-2,7-diazaspiro[3.5]nonan-7-y1]-2-(2,6-cliox0-piperidypisoindoline-1,3-dione tritrifluoroacetate (compound 7) NH
3CFaCOOH

141-[(2-chloropyrimidin-5 -y1) methy1]-4-piperi dy1]-3 -(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine (7c) (0.2 g, 0.39 mmol) was Date Recue/Date Received 2021-09-09 dissolved in 2 mL of DMF. At room temperature, 5-(2,7-diazaspiro[3.5]nonan-7-y1)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione hydrochloride (7b) (0.32 g, 0.78 minol) and triethylamine (0.15 g, 1.55 annol) were added, and the mixture was warmed to 80uC and reacted for 5 h. The reaction solution was poured into 50 mL of water, the aqueous phase was extracted with dichloromethane/methanol (v/v) =
10 :
1 (50 int x 3), and the organic phase was combined, washed with 50 niL of water, dried over anhydrous sodium sulphate, and concentrated. The crude product was passed through Pre-HPLC (instrument and preparative column: using Glison GX-to prepare the liquid phase, preparative column model: Sunfire C18, 5 p.m, inner diameter x length = 30 mm x150 mm). Preparation method: The crude product was dissolved with methanol and dimethyl sulphoxide, and filtered with 0.45 um filter membrane, to prepare into a sample solution. Mobile phase system:
acetonitrile/water (containing 0.1% TFA). Gradient elution method: gradient elution with acetonitrile from 5% to 60% (elution time: 15 min), the reaction system was lyophilized to obtain 5-[2-[5- [[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo [3 ,4-d]pyrim idin-l-y1]-1-piperidyl ]methylipyrimidin-2-y1]-2,7-di azaspiro[3.5]nonan-7-y1]-2-(2,6-dioxo-piperidyl)isoindol ine-1,3-dione tritrifluoroacetate (compound 7) (0.08 g, yield: 20%).
IF1 NMR (400 MHz, CD30D) 8 8.48 (s, 2H), 8.42 (s, 1H), 7.65 (t, 3H), 7.45-7.37 (m, 2H), 7.33 (d, 1H), 7.27-7.13 (in, 4H), 7.13-7.05 (m, 2H), 5.31-5.17 (m, 1H), 5.05 (dd, 1H), 4.31 (s,2H), 3.96 (s, 4H), 3.73 (d, 2H), 3.54-3.43 (m, 4H), 3.43-3.31 (m, 2H), 2.90-2.54 (in, 5H), 2.41 (s, 2H), 2.16 - 2.02 (m, 1H), 1.99-1.88 (m, 4H).
LCMS m/z = 859.3 [M+1]'.
Example 8:
5-(3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-l-y1)-[1,4'-bipiperi din] -11-yl)azefi din-1 -y1)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione tritritluoroacetate (compound 8) H2N \ IN
o 0 Cj) 3GF3COOH

Date Recue/Date Received 2021-09-09 .0:00;21)c,N

1.12N 0' IP
Step 2 N- N
N-1.4 ¨N
2b Bb Ba NH NBoc H2N \
Step 3 \ o 'UF1 Compound 8 0 Step 1:
Tert-butyl 3-(4-(4-amino-3-(4-pbenoxypheny1)-1 H-pyrazolo[3,4-d]pyrimidin-s 1 -y1)-[ 1,4'-bipiperidi n1-1 t-yl)azetidine-1 -carboxylate (8a) NN
o ()N
N Btx;
3-(4-phenoxypheny1)-1-[1 -(4-piperidy1)4-pi peridyl] pyrazolo [3,4-d]
pyrimidin-4-amine (2b) (0.256 g, 0.545 mmol) was dissolved in 20 mL of 1,2-dichloroethane, and glacial acetic acid (0.049 g, 0.818 mmol) and tert-butyl 3-oxoazetidine-1-carboxylate (0.131 g, 0.763 mmol) were successively added. Under nitrogen atmosphere, the mixture was heated to 65 C, stirred and reacted for 3 h, then cooled to room temperature, followed by addition of sodium triacetoxyborohydride (0.693 g, 3.27 mmol), and the mixture was stirred at room temperature overnight. The reaction was quenched by adding 20 mL of saturated sodium bicarbonate solution, stirred, and allowed to stand for layer separation. The aqueous phase was extracted with dichloromethane (15 mL x 2), and the organic phase was combined, washed with 30 mL of saturated saline, dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) ¨ 100/1-15/1), Date Recue/Date Received 2021-09-09 to obtain tert-butyl 34444- amino-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-d]pyrimidin-l-y1)41,4t-bipiperidin]-1'-yl)azetidine-1-carboxylate (8a) (0.301 g, yield:
88%).
Step 2:
-(lr-(azetidin-3-y1)41,4'-bipiperidin]-4-y1)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d}pyrimidin-4-amine (8b) NN
/
¨N
NH
Tert-butyl 3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-djpyrimidin-l-y1)-[1,4t-bipiperidini-1'-y1)azetidine-1-carboxylate (8a) (0.301 g, 0.482 mmol) was dissolved with 2 mL of methanol, and 10 mL of 4 N ethyl acetate hydrochloride solution was added dropwise, the mixture was reacted at room temperature overnight.
The reaction solution was concentrated under reduced pressure to obtain a crude product, and the pll of the crude product was adjusted to 9-10 with saturated sodium bicarbonate solution, which was extracted with dichloromethane (20 mL x 3).
The is organic phase was combined, dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to obtain 1-(1'-(azctidin-3-y1)41,4'-bipiperidini-4-y1)-3 -(4-phenoxypheny1)-1H-pyrazolo[3 ,4-d] pyrimidi n-4-am ine (8b) (0.239 g, yield: 70%).
Step 3:
5-(3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-d] pyrim idin-l-y1)-[1,4'-bipiperi din]-11-yl)azetidin-l-y1)-2-(2,6-dioxopiperidin-3-y1)isoindoline-1,3-dione tritrifluoroacetate (compound 8) Date Recue/Date Received 2021-09-09 H2N \ I
N¨C /
N = 0 -N

1-( lt-(azeti din-3-y1)-[ I ,4'-bipiperidin]-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d}pyrirnidin-4-amine (8b) (0.239 g, 0.456 mmol) was dissolved in mL of dimethyl sulphoxide, and NN'-diisopropylethylamine (0.295 g, 2.28 mmol) and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO

for the synthetic method) (0.164 g, 0.592 mmol) were successively added, and the mixture was heated to 90 C and reacted for 6 h under nitrogen atmosphere. To the reaction solution was added 10 mL of water, a solid was precipitated out, filtered off with suction, and the filtrate was extracted with ethyl acetate (40 mL x 2).
The organic phase was combined, washed with 50 mL of saturated saline, dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 100/1-20/1), to obtain a crude product. The crude product was passed through Pre-HPLC (instrument and preparative column: using Glison GX-281 to prepare the liquid phase, preparative column model: Sunfire C18, 5 pm, inner diameter x length = 30 mm x150 mm). Preparation method: The crude product was dissolved with methanol and dimethyl sulphoxide, and filtered with 0.45 um filter membrane, to prepare into a sample solution. Mobile phase system:
acetonitrile/water (containing 0.1% TFA). Gradient elution method: gradient elution with acetonitrile from 5% to 60% (elution time: 15 min), the reaction system was lyophilized to obtain 5-(3-(4-(4-amino-3-(4-phenoxypheny1)-111-pyrazolo[3,4-d]pyrim idin-l-y1)-11,4t-bipiperidini- I '-yl)azetidin- 1 -y1)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione tritrifluoroacetate (compound 8) (0.207 g, yield:
40%).
1H NMR (400 MHz, DMSO-d6) 6 11.07 (s, 1H), 8.34 (s, 1H), 7.72 (d, 1H), 7.66 (d, 2H),7.45 (t, 2H), 7.23-7.09(m, 5H), 6.89(s, 1H), 6.75(d, 1H), 5.I9-5.04(m, 2H), 4.40 - 4.05 (1n, 7H), 3.76-3.27 (m, 7H),2.97-2.75 (m, 2H), 2.64-2.52 (m, 3H), 2.40-2.19 (m, 4H), 2.08-1.79(m, 3H).
Date Recue/Date Received 2021-09-09 LCMS m/z = 781.3 [M+1]
Example 8-1:
5-(3 -(4-(4-amino-3 -(4-plienoxypheny1)-1H-pyrazolo [3,4-d]pyrimidi -y1)-[1,4'-bi piped din -1'-yl)azeti din-1 -yl )-2-(2,6- di oxopi peridi soindo line-1,3-dione (compound 8-1) N2N\ /

N
1.1 0 The compound 8 (2 g) was dissolved in 50 mL of dichloromethane, and the mixed solution was washed with concentrated ammonia water with a mass fraction of 28% (50 mL x 5). The organic layer was dried over anhydrous sodium sulphate, and concentrated under reduced pressure. To the residue was added 20 mL of ethyl acetate, stirred for 3 h, and filtered, and the filter cake was vacuum-dried, to obtain the free base 5-(3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-l-y1)41,4'-bipiperidini-1'-ypazetidin- I -y1)-2-(2,6-dioxopiperidin-3-ypisoindoline-1,3-dione (compound 8-1) (1.3 g).
'H NMR (400 MHz, CDC13) 6 10.22 (brs, 1H), 8.39 (s, 1H), 7.67 - 7.60 (m, 3H), 7.42 - 7.34 (m, 2H), 7.19 - 7.10 (m, 3H), 7.10- 7.04 (in. 2H), 6.78 (d, 1H), 6.51 (dcl, 1H), 5.89 (brs, 2H), 4.96 - 4.88 (m, 1H), 4.83 -4.70 (m, 1H), 4.14 -4.04 (in, 2H), 3.92 - 3.84 (m, 211), 3.39 - 3.30 (m, 111), 3.18 - 3.04 (in, 211), 3.00- 2.91 (in, 211), 2.90 - 2.65 (m, 3H), 2.56 - 2.32 (m, 5H), 2.16 - 2.01 (m, 3H), 2.01 - 1.84 (in, 4H), 1.73 - 1.59 (in, 2H).
LC-MS m/z = 781.4 [M 1]*.
Example 9:
5-(4-((4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazol o [3,4 -d] pyrim id in-1-yl)piperidin-1 -yl)methy1)11,4'-b ipiperidinj -1'-y1)-2-(2,6-dioxopiperidin-3 yl)isoindoline-1,3-dione tetratrifluoroacetate (compound 9) Date Recue/Date Received 2021-09-09 / S) (Y ---N
N¨N

( NH
N

(\ -N-Thr \

ON .. "2" N H2N N
,. \?---÷,. ---00 IIP irrni riPs.
..:-.---N cr 1 S{,p 2 Of, NH 9a \--CN¨CN¨Eicso 9b \¨CN¨CNH
0 ,..Lvl-bN N...
1 ,f-N
Ng; 3 N¨N 4CF3COOH
rff liN
Compeund 9 Step 1:
Tert-butyl 4-((4-(4-amino-3-(4-phenoxypheny1)- I H-pyrazolo[3,4-djpyrimidin-1-y1 )pipericlin- I -yl)methy1)41,4'-bipiperidinei-l'-carboxylate (9a) H2N _N

N¨N
N\ __ K N \ --( \N ¨Boc / /
3-(4-phenoxyphenyi)- 1 -( 1 -(piperi din-4-ylmethyl)p iperidin-4-y1)- 111-pyrazolo[3,4-dipyrirnidin-4-amine (6b) (0.44 g, 0.91 mmol) was dissolved in 10 mL
of 1,2-dichloroethane, and tert-butyl 4-oxopiperidine-1 -carboxylate (0.24 g, lA 8 mmol) was added at room temperature, the mixture was heated to 50 C, stirred for lh, and then cooled to room temperature. To the reaction solution was added sodium triacetoxyhorohydride (0.48 g, 2.28 mmol), and the mixture was reacted at room temperature overnight. The reaction solution was poured into 50 mL of saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate (50 mL X 3), and the organic phase was combined, washed with water (50 mL X 2), dried over anhydrous sodium sulphate, and concentrated, to obtain tert-butyl 44(4-0-Date Recue/Date Received 2021-09-09 am ino-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-d]pyrimidin-1-y 1)piperidin- I -yl)methy1)41,41-bipiperidine]-1'-carboxylate (9a) (0.31 g, yield: 51%).
LCMS in/z ¨ 667.4 [M-F
Step 2:
1-( I -([1,4'-bipiperidin]-4-ylmethyl)piperidin-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-am inc (9b) Alt, NN
L') ___________________________________________ N
N---( \NH
Tert-butyl 4-((4-(4-amino-3-(4-phenoxypheny1)-111-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-y1)methyl)41,4'-bipiperidinej-1'-carboxyl ate (9a) (0.31 g, 0.46 mmol) was dissolved in 6 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 2 h. The pH was adjusted to 9-10 with 20 mL of 2 N sodium hydroxide aqueous solution, the aqueous phase was extracted with dichloromethane (10 mL x 3), and the organic phase was dried over anhydrous sodium sulphate, and concentrated, to obtain 1-(1-([1,4'-bipiperidin]-4-ylmethyl)piperidin-4-y1)-3-(4-phenoxypheny1)-1H-pyrazo1o[3,4-d]pyrimidin-4-amine (9b) (0.17 g, yield: 65%).
LCMS m/z = 567.4 Step 3:
5-(4-((4-(4-amino-3-(4-phenoxypheny1)- IH-pyrazolo[3,4-d]pyrimidin-1 yl)piperidin-l-yl)methyl)41,4'-bipiperidin]-1'-y1)-2-(2,6-dioxopiperidin-3-y1)isoindoline-1,3-dione tetratrifluoroacctate (compound 9) Asti 0ç1110 N-N

N\ ___________________________________ ()N \N 0 i-(1 -([1,4'-bipiperidin]-4-ylmethyl)piperidin-4-y1)-3 -(4-phenoxypheny1)-1H-Date Recue/Date Received 2021-09-09 pyrazolo[3,4-d]pyrimidin-4-amine (9b) (0.17 g, 0.3 mmol) was dissolved in 5 mL
of DMSO, and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO
2017197056 for the synthetic method) (0.1 g, 0.36 nunol) and N,N'-diisopropylethylamine (0.3 g, 2.3 mmoi) were added at room temperature, and the mixture was warmed to 80 C and reacted for 3 h. The reaction solution was poured into 20 mL of water, the aqueous phase was extracted with dichloromethane/methanol (v/v) = 10 : 1 (30 mL x 31), and the organic phase was combined, washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated. The crude product was passed through Pre-IIPLC (instrument and preparative column: using Glison GX-281 to prepare the liquid phase, preparative column model: Sunfire C18, 5 pm, inner diameter x length = 30 mmx 150 mm).
Preparation method: The crude product was dissolved with methanol and dimethyl sulphoxide, and filtered with 0.45 pm filter membrane, to prepare into a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% TFA).
Gradient elution method: gradient elution with acetonitrile from 5% to 60% (elution time: 15 min), the reaction system was lyophilized to obtain 5-(4-((4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazo lo [3 ,4-d]pyrimidin -1 -yl)piperidi n-1 -y 1)inethyl)- [1,4'-bipiperidin]-1'-y1)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione tetratrifluoroacetate (compound 9) (0.11 g, yield: 45%).
1H NMR (400 MHz, DMSO-d6) 6 11.06 (s, 1H), 9.46 (d, 2H), 8.32 (s, 1H), 7.72 - 7.55 (m, 3H), 7.47 -7.41 (m, 3H), 7.35 -7.29 (m, 1H), 7.22 - 7.12 (m, 5H), 5.10 -5.05 (m, 2H), 4.26 (d, 2H), 3.71 (d, 2H), 3.63 - 3.39 (m, 4H), 3.32 - 3.17 (rn, 2H),3.07 -2.85 (m, 6H), 2.65 -2.51 (m, 4H), 2.32 - 1.94 (in, 8H), 1.72 - 1.69 (m, 2H), 1.48 -1.45 (m, 2H).
LCMS ni/z ¨ 412.3 [M/2 1] .
Example 10:
5-(4-(3-((4-(4-am ino-3 -(4-phenoxyphen y1)-1H-pyrazolo [3 ,4-cl]pyrim idin-1 -yl)piperidin-1 -yl)methyl)azetidin-1 -yl)piperi din-l-y1)-2-(2,6-dioxopiperidin-3 -ypisoindoline-1,3-dione tetratrifluoroacetate (compound 10) Date Recue/Date Received 2021-09-09 H2N _N

N-N
L,) 4CF3COOH 0 N
N,-----õ,õõ NH
\N

QH

110 C;o,110 '\PI
N-N Sit.p 1 , Ur --- N Szep 2 --1-12N--"N b \--N-Boc \ __ , 'NH
la \...."
10a 1 Ob r` \
Stcp 3 \
Step 4 ep 5 N-N N-N

10c \¨CN 10r1 ¨CN¨Boc \---N¨CNH

,o a N õrill 1-r--N
Compound 10 \----CN-C \NI 0 Step 1:
Tert-butyl 3-((4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-s I -yl)piperidin-1 -yOmethypazetidine- 1 -carboxylate (10a) /
\
N-N
L ') N \ c _______________________________________________ N-Boc 3-(4-phenoxypheny1)-1-(piperidin-4-y1)-1H-pyrazo1 o [3,4-d]pyrim idin-4-am ine (la) (see J. Med. Chem. 2015, 58, 9625-9638 for the synthetic method) (0.5 g, 1.29 mmol) was dissolved in 15 mL of DME, and tert-butyl 3-formylazetidine-1-carboxylate (0.31 g, 1.68 mmol) was added at room temperature, the reaction was Date Recue/Date Received 2021-09-09 stirred at room temperature for 0.5 h, and then sodium triacetoxyborohydride (0.68 g, 3.22 mmol) was added, and the mixture was stirred at room temperature overnight.
To the reaction solution was added 50 mL of water, the aqueous phase was extracted with dichloromethane (30 mL x 3), and the organic phase was combined, washed with water (20 mL x 2), dried over anhydrous sodium sulphate, and concentrated.
The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 100 : 1-20 : 1), to obtain tert-butyl 34(444-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-1-yl)methyl)azeti dine-1-carboxyl ate (10a) (0.65 g, yield: 91%).
LCMS m/z = 556.4 [M+1] .
Step 2:
1-(1-(azetidin-3-ylmethyl)pi peri din-4-y1)-3-(4- phenoxypheny1)- 1H-pyrazolo13 ,4-d}pyrimidin-4-amine (10b) çHN -N
= cç
N-N
CNH
Tert-butyl 34(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazo lo [3 ,4-djpyrimidin-1-yl)piperidin-l-yOm ethypazeti dine-l-earboxylate (10a) (0.61 g, 1.17 mmo I) was dissolved in 6 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 2 h. The pH was adjusted to

9-10 with 20 mL of 2 N sodium hydroxide aqueous solution, the aqueous phase was extracted with dichloromethane (10 mL x 3), and the organic phase was dried over anhydrous sodium sulphate, and concentrated, to obtain 1-(1-(azetidin-3-ylm ethyl)p ip eridi n-4-y1)-3-(4-phenoxyph eny1)-1H-pyrazolo [3,4-d] pyrimidi n-4-amine (10b) (0.47 g, yield: 89%).
LCMS m/z = 456.3 [M+1]'.
Step 3:
Tert-butyl 4-(3-((4-(4-amino-3 -(4-phenoxypheny1)-1H-pyrazolo[3 ,4-d]pyrim idin-l-yl)piperidi n-l-yl)methyl)azetidi n-1 -yl)piperi dine- I -carboxyl ate (10c) Date Recue/Date Received 2021-09-09 NN
CN¨K _________________________________________________ 1N¨Boc 1-(1-(azetidin-3-ylmethyl)piperidin-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (10b) (0.47g, I .03 mmol) was dissolved in 10 mL
of 1,2-dichloroethane, and tert-butyl 4-oxopiperidine-l-carboxylate (0.27 g, 1.34 mmol) was added at room temperature, and the mixture was heated to 50 C, stirred for I h, and then cooled to room temperature. To the reaction solution was added sodium triacetoxyborohydride (0.55 g, 2.58 mmol), and the mixture was reacted at room temperature overnight. The reaction solution was poured into 50 mL of saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate (50 mL x 3), and the organic phase was combined, washed with water (50 mL
x 2), dried over anhydrous sodium sulphate, and concentrated, to obtain tert-butyl 4-(34(444- am in o-3-(4-ph en oxyph eny1)-1H-pyrazolo[3,4-d]pyrimidin- I -yppiperidin-1-y1 )methyl)azeti din-l-yl)piperidine-1-carboxylate (10c) (0.31 g, yield:
48%).
LCMS m/z = 639.8 [M+1]f.
Step 4:
3-(4-phenoxypheny1)-1-(1 -((1 -(piperidin-4-yl)azetidin-3-yl)methyl)pip eridin-4-y1)-1H-pyrazolo [3 ,4-d]pyrimidi n-4-amine (10d) ¨ N
NN
CN¨( _________________________________________________ \NH
Tert-butyl 4-(3 4(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-1 -yl)methypazetidin-1-yppiperidine-1-carboxylate (10c) (0.31 g, 0.49 mmol) was dissolved in 6 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 2 h. The pH was adjusted to 9-10 with 20 mL of 2 N sodium hydroxide aqueous solution, the aqueous phase was extracted with diehloromethane (10 mL x 3), and the Date Recue/Date Received 2021-09-09 organic phase was dried over anhydrous sodium sulphate, and concentrated, to obtain 3 -(4 -phenoxypheny1)-1-(1-((1-(piperidin-4-yl)azetidin-3-y1)methyl)piperidin-4-y1)-1H-pyrazolo [3 ,4-djpyrimidin-4 -amine (10d) (0.18 g, yield: 65%).
LCMS m/z = 539.7 [M+11 .
Step 5:
5-(4-(34(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-1-y1)piperidin-1-y1)methyl)azetidin-1-y1)piperidin-1-y1)-2-(2,6-dioxopiperidin-3-ypisoindoline-1,3-dione tetranifluoroacetate (compound 10) \ I :IN
N-N

8 10 3-(4-phenoxypheny1)-1-(1-((1-(piperidin-4-yl)azetidin-3-y1)methyl)piperidin-4-y1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (10d) (0.18 g, 0.34 mmol) was dissolved in 5 mL of DMSO, and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (0.12 g, 0.37 mmol) and N,AP-diisopropylethylamine (0.3 g, 2.3 mmol) were added at room temperature, the mixture was warmed to 80 C and reacted for 3 h. The reaction solution was poured into 20 mL of water, the aqueous phase was extracted with diehloromethane/methanol (v/v) - 10 : 1 (30 itiL x 3), and the organic phase was combined, washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated. The crude product was passed through Pre-HPLC (instrument and preparative column: using Glison GX-281 to prepare the liquid phase, preparative column model: Sunfire C18, 5 pm, inner diameter x length = 30 mmx 150 mm).
Preparation method: The crude product was dissolved with methanol and dimethyl sulphoxide, and filtered with 0.45 p.m filter membrane, to prepare into a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% TFA), Gradient elution method: gradient elution with acetonitrile from 5% to 60% (elution time: 15 min), the reaction system was lyophilized to obtain 5-(4-(34(4-(4-amino-3-(4-phenoxyphenyI)-1H -pyrazo lo[3 ,4-d]pyrim idin-1 -yl)pi peridi n-1 -yOmethyl)azetidin-Date Recue/Date Received 2021-09-09 -yl)piperidin-l-y1)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione tetratrifluoroacetate (compound 10) (0.13 g, yield: 48%).
1H NMR (400 MHz, DMSO-d6) 6 11.06 (s, 1H), 8.31 (s, 11), 7.72-7.54 (m, 3H), 7.48-7.39 (m, 3H), 7.33-7.31 (m, 1H), 7.24-7.09 (m, 5H), 5.10-5.05 (m, 3H), 4.25-4.08 (m,7H), 3.70-3.38 (m, 6H), 3.01-2.89 (m, 3H), 2.69-2.39 (m, 4H), 2.22-2.19 (m, 2H), 2.10-1.89 (in, 3H), 1.41-1.39 (m, 2H).
LCMS m/z = 398.3 [M/2 +1r.
Example 11:
5-[4-[4- [4-[3-[4-[4-amino-3-(4-phenoxypheny1)pyrazolo[3,4-djpyrimidin-1-y11-1-piperidyl]azetidin-1-y1]-1-piperidy1]-1-piperi dyl] -1-pi peri dy1]-2-(2,6-di oxo-3-piperidyl)isoindoline-1,3-dione hexatrifluoroacetate (compound 11) /

r.,Nt p,Nr_CiN-&/

N="f Cc) a ,N,NOH Step f N,N St.p 2 0 Z.¨a ,N,N
13N¨"CIIH Step 1-1,N-774'N
N1=1 N=i lla lib Date Recue/Date Received 2021-09-09 q=.õ-.Eiac q.
r_m, jo,Boc 11C 11c1 N=

__CIN,Boc p _c__-_,,, P

Step(' 0 Step 7 _fisr-C¨J¨NWCIN Step S

N 01----j _.- )4.N"Grli ¨1.-N=ir 111 lµi 119 p ¨
_Ci=N-C _Cj --t__,./0 N__UN
a . N.N..0,-4-j a- 0 ,N_N_CIN
µ

N=i 11h N=/
Step 1:
Tert-butyl 34444-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin- I -yI]-1-piperidyliazetidine-l-carboxylate (1 I a) p Boc H2N)' N
N=/
3-(4-phenoxyphenyl )-1-(piperidin-4-y1)-1H-pyrazolo[3,4-dipyrimidin-4-amine (1a) (see ,I. Med. Chem. 2015, 58, 9625-9638 for the synthetic method) (0.500 g, 1.29 mmol) was dissolved in 5 inL of 1,2-dichloroethane, and tert-butyl 3-oxoazetidine-1-carboxylate (0.266 g, 1.55 mmol) and glacial acetic acid (0.412 g, 6.86 mmol) were added. Upon completion of the addition, the reaction was stirred at 65 C for 3 h, then cooled to room temperature, and sodium triacetoxyborohydride (0.548 g, 2.59 mmol) was added. Upon completion of the addition, the reaction was carried out at room temperature overnight. The pH was adjusted to 9-10 by adding dropwise saturated sodium bicarbonate solution. The reaction solution was concentrated under reduced pressure, and then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 100 : 0-19 : 1), to obtain tert-Date Recue/Date Received 2021-09-09 butyl 314- [4-amino-3-(4-phenoxyphenyl)pyrazolo [3 ,4-d] pyrimidin-l-y11-1-piperidyllazetidine- 1-carboxylate (ha) (0.700 g, yield: > 99%).
LCMS in/z ¨ 542.3 [M-Fir.
Step 2:
1 -[ I -(azetidin-3-y1)-4- piperidy I] -3-(4-phenoxyph enyl) pyrazolo [3 ,4-d]pyrimidin-4-amine (11 b) 0 jut \ H2N N
Tert-butyl 3-[4-[4-ami no-3 -(4-phenoxyphenyl)pyrazolo[3 ,4-d] pyri mi d in-l-y11-1-piperidyliazetidine- -carboxylate (11a) (0.700 g, 1.29 mmol) was dissolved in 2 mL of dichlorornethane, and 5 mL of 4 N ethyl acetate hydrochloride solution was added, the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, and then to the residue was added 20 mL
of dichloromethane. The pH was adjusted to 9-10 with saturated sodium bicarbonate solution. The liquid separation was conducted, and the organic layer was dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain (azetidin-3- y1)-4-pipericly1j- 3-(4-phenoxyphenyl)pyrazo lo [3,4-djpyrimid in-4-amine (11 b) (0.410 g, yield: 72%).
LCMS m/z 442.2 [M 1]+.
Step 3:
Tert-butyl 44314-[4-amino-3-(4-phenoxyphenyl)pyrazolo [3 ,4-d]pyrimidin-1-yl] -1-piperidyl] azetid in-l-Apiperidine-l-carboxyl ate (11c) ci?BOO
N
N , N
H2N = \N
N¨/
141-(azetidin-3-y1)-4-piperidy1]-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine (11 b) (0.410 g, 0.929 minol) was dissolved in 5 !I-IL of 1,2-dichloroethane, and tert-butyl 4-oxopiperidine-1-carboxylate (0.222 g, 1.11 mmol) Date Recue/Date Received 2021-09-09 and glacial acetic acid (0.296 g, 4.92 mmol) were added. Upon completion of the addition, the reaction was stirred at 65 C for 3 h, then cooled to room temperature, and sodium triacetoxyborohydride (0.394 g, 1.86 minol) was added. Upon completion of the addition, the reaction was carried out at room temperature overnight. The pH was adjusted to 9-10 by adding dropwise saturated sodium bicarbonate solution. The reaction solution was concentrated under reduced pressure, and then the crude product was separated and purified by silica gel column chromatography (dichloromethanc/methanol (v/v) = 100 : 0-19 : 1), to obtain tert-butyl 44344- [4-amino-3-(4-ph enoxyphenyl)pyrazolo [3 ,4-d[pyrimi din-1-y1]-1-piperidyl]azetidin-1-yl]piperidine-1 -carboxylate (1 I e) (0.380g. yield:
66%).
11-1 NMR (400 MHz, CDC13) 6 8.35 (s, 1H), 7.67-7.61 (m, 2H), 7.43-7.35 (m, 21-1), 7.21-7.12 (in, 311), 7.11-7.05 (in, 21-1), 5.56 (br, 211), 4.82-4.72 (m, 1H), 4.07-3.93 (m, 211), 3.72-3.55 (m, 2H), 3.15-2.87 (in, 5H), 2.81 (t, 2H), 2.49-2.35 (in, 2H), 2.17-1.97 (in, 51-1), 1.75-1.67 (in, 2H), 1.45 (s, 9H), 1.35-1.25 (m, 211).
Step 4:
3-(4-phenoxypheny1)-1-[ I -[ 1-(4 -piperidyl)azet idi n-3 -y1]-4-piperidylipyrazolo [3 ,4-d]pyrimidin-4-am ine (11d) N, N
\ H2N N
Tert-butyl 4-[3 -[4 -[4 -amino-3 -(4-phenoxyphenyl) pyrazolo [3 ,4 -d]pyri midin-1-y1]-1-piperidyl]azetidin-l-yl]piperidine-1-carboxylate (11c) (0.380 g, 0.608 rnmol) was dissolved in 2 mL of dichloromethane, and 5 mL of 4 N ethyl acetate hydrochloride solution was added, the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, and then to the residue was added 20 mL of dichloromethane. The pH was adjusted to 9-10 with saturated sodium bicarbonate solution. The liquid separation was conducted, and the organic layer was dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain 3-(4-phenoxypheny1)-1-[1 -[1-(4 -pi peridypazetidi n-3 -y1]-Date Recue/Date Received 2021-09-09 4-piperidylipyrazolo[3,4-d]pyrimidin-4-amine (11d) (0.256 g, yield: 80%).
LCMS m/z = 263.3 [M/2 +1]+.
Step 5:
Tert-butyl 444434444-amino-3-(4-phenoxyphenyppyrazolo[3,4-d[pyrimidin-s 1-y1]-1-p iperidyl]azetid in-1-y1]-1-p peridyl]p iperid ne-l-carboxylate (1 1 e) Bo c I-12N \CN
N=/
3-(4-phenoxyphenyI)-1 -[1-[ I -(4-piperidypazetidin-3-y1]-4-piperidyllpyrazolo[3,4-d]pyrimidin-4-amine (11d) (0.256 g, 0.488 mmol) was dissolved in 3 mL of 1,2-diehloroethane, and tert-butyl 4-oxopiperidine-1-3.0 carboxylate (0.117 g, 0.585 mmol) and glacial acetic acid (0.155 g, 2.59 mmol) were added. Upon completion of the addition, the reaction was stirred at 65 C for 3 h, then cooled to room temperature, and sodium triacetoxyborohydride (0.207 g, 0.976 mmol) was added. Upon completion of the addition, the reaction was carried out at room temperature overnight. The pH was adjusted to 9-10 by adding dropwise saturated 15 sodium bicarbonate solution. The reaction solution was concentrated under reduced pressure, and then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 100 : 0-19 : 1), to obtain tert-butyl 4444314- [4-am ino-3-(4-phenoxyph enyl)pyrazolo [3,4-dlpyrimidin-l-y11-1-piperidyl]azetidin-l-y1]-1-piperidyl]piperidine-l-carboxylate (1 1 e) (0.244 g, yield:
20 71%).
LCMS m/z = 708.5 [M+1]t Step 6:
3-(4-phenoxypheny1)-1 4 1 4 l 4 1 -(4-piperidy1)-4-pi peri dyl] azeti din-3-yI]-4-piped dyl]pyrazolo[3 ,4-d]py rim idin-4-amine (110 NH
0 Alik _CN---CN
µN

25 N=/
Date Recue/Date Received 2021-09-09 Tert-butyl 4444344-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-y1]-1 -piperidyl] azetidin-l-yl] -1-piperidyl]piperidine-l-carboxylate (1 1 e) (0.244 g, 0.345 inmol) was dissolved in 2 InL of dichloromethane, and 5 inL of 4 N ethyl acetate hydrochloride solution was added, the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, and then to the residue was added 20 niL of dichloromethane. The pH was adjusted to 9-10 with saturated sodium bicarbonate solution. The liquid separation was conducted, the aqueous layer was extracted with 100 InL of dichloromethane/methanol (v/v) = JO: 1, and the organic layers were combined, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain 3-(4-phenoxypheny1)-1-[1-[1-[1-(4-pi peridy1)-4-pi peri dyl]azeti din-3 -yl] -piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (111) (0.209 g, yield: >99%).
LCMS m/z = 304.8 [M/2 +-11+.
Step 7:
Tert-butyl 4-[4-[4-[3-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-y1]-1-piperidyl]azetid in-l-y1]-1-piperidy1]-1-piperidyl]piperidine-l-carboxylate (11g) N_Boc OJON
o_ H2N) N-=-1 3-(4-phenoxyphenyI)-1- [1-[1- [1-(4-piperidy1)-4-piperi dyl[azeti din-3-y1]-4-piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (11f) (0.208 g, 0.342 mmol) was dissolved in 3 mL of 1,2-dichloroethane, and tert-butyl 4-oxopiperidine- 1 -carboxylate (0.102 g, 0.513 minol) and glacial acetic acid (0.109 g, 1.81 minol) were added. Upon completion of the addition, the reaction was stirred at 65 C for 3 h, then cooled to room temperature, and sodium triacetoxyborohydride (0.145 g, 0.684 minol) was added. Upon completion of the addition, the reaction was carried out at room temperature overnight. The pH was adjusted to 9-10 by adding dropwise saturated sodium bicarbonate solution. The reaction solution was concentrated under reduced Date Recue/Date Received 2021-09-09 pressure, and then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 100 : 0-7 : 3), to obtain tert-butyl 44444434444-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-l-y1]-1-piperidyl jazetidin-1-y1 j- I -piperidy1]-1-piperidyl jpiperidine-l-carboxylate (11g) (0.152 g, yield: 56%).
LCMS in/z ¨ 396.3 [M/2 +1]+.
Step 8:
3-(4-phenoxypheny1)-1-[1-[1-[141 -(4-piperidy1)-4-piperidy1]-4-piperidyliazetidin-3-y1]-4-piperidylipyrazolo[3,4-d]pyrimidin-4-amine (11h) õINH
0 ¨C
N
H2N/ \N
N=i Tert-butyl 44444434444-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-l-y1]-1-piperidygazetidin-l-y11-1-piperidy1]-1-piperidyl]piperidine-l-carboxylate (1 g) (0.152 g, 0.192 mmol) was dissolved in 2 mL of dichloromethane, and 5 ml. of 4 N ethyl acetate hydrochloride solution was added, and the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, and then to the residue was added 20 mL of diehloromethane.
The pH was adjusted to 9-10 with saturated sodium bicarbonate solution. The liquid separation was conducted, the aqueous layer was extracted with 100 mL of dichlorornethane/methanol (v/v) =. 10: 1, and the organic layers were combined, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain 344-phenoxypheny1)-141-[14141-(4-piperidy1)-4-piperidy1]-4-piperidy1lazetidin-3-y1]-4-piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (11h) (0.133 g, yield:
>99%).
LCMS m/z = 346.4 [M/2 +IT.
Step 9:
54444- [4- [34444-amino-3 -(4-phenoxyphenyl)pyrazolo [3,4-d] pyrimidin-1 ylj- I -piperidyljazetidin-l-y1.1-1-piperidy1]-1-piperidy11-1-piperidy1]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione hexatrifluoroacetate (compound 11) Date Recue/Date Received 2021-09-09 N, N"-=/
3 -(4-phenoxypheny1)- 1 [ 1 4 1 '414 1 (4-pi peri dy1)-4-piperi dy 1]-4-piperidyljazetidin-3-y1]-4-piperidyljpyrazolo[3,4-d]pyrimidin-4-amine (1111) (0.130 g, 0.188 mmol) was dissolved in 2 tiriL of ditnethyl sulphoxide, 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (0.0676 g, 0.245 mmol) and diisopropylethylamine (0.122 g, 0.941 mmol) were added. Upon completion of the addition, the reaction was stifled at 90 C for 2 h. The reaction solution was cooled to room temperature, to which 10 nil_ of water was slowly added dropwise, and filtered. The filter cake was dissolved with 20 mL
of dichloromethane, then washed with 5 mL of saturated sodium chloride solution.
The liquid separation was conducted, and the organic layer was dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was passed through Pre-HPLC (instrument and preparative column: using Glison GX-281 to prepare the liquid phase, preparative column model: Sunfire C18, 5 tin, is inner diameter x length = 30 mmx 150 mm). Preparation method: The crude product was dissolved with methanol and dimethyl sulphoxidc, and filtered with 0.45 um filter membrane, to prepare into a sample solution. Mobile phase system:
acetonitrile/water (containing 0.1% TFA). Gradient elution method: gradient elution with acetonitrile from 5% to 60% (elution time: 15 min), the reaction system was lyophilized to obtain 5444414-[34444-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-l-y1]-1-piperidyl]azetidin-1-y1]-1-piperidy11-1-piperidy1]-1-piperidy1]-2-(2,6-dioxo-3-piperidypisoindoline-1,3-dione hexatrifluoroacetate (compound 11) (0.013 g, yield: 4%).
111NMR (400 MHz, DMSO-d6) 6 11.06 (s, 1H), 8.28 (s, 1H), 7.78-7.62 (m, 4H), 7.47-7.40 (m, 214), 7.36-7.28 (m, 1H), 7.26-7.06 (m, 5H), 5.08 (dd, 114), 4.89-4.78(m, 1H), 4.31-4.10 (in, 5H), 4.04-3.88 (m, 4H), 3.68-3.45 (in, 6H), 3.07-2.81 (m, 6H), Date Recue/Date Received 2021-09-09 2.65-2.53 (m, 211), 2.41-1.82 (m, 1211), 1.76-1.48 (m, 511), 1.32-1.21 (m, 4H).
LCMS m/z = 474.4 [M/2 +1].
Example 12:
5-14-14-[4-14-14-amino-3-(4-phenoxyphenyl )pyrazolo13,4-djpyrimidin-l-y11-1--piperidy1]-1 -piperidylj- 1 -piperidy11- 1 -piperidy1]-2-(2,6-dioxo-3 -piperidypisoindoline-1,3-dione pentatrifluoroacetate (compound 12) =

N

H3N \ N
Wil 1111 NBoc Stcp -NIN
,CN I-4,r1/2 1,1=/
2d N=f 12a 11, N ,c? t)¨K0A

Step 3 0 N

F1 120 H2N \N =7 r4=7 Compound 12 Step 1:
Tert-butyl 444144444-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1 -y11-1 -piperidy11-1 - piperidy11-1-piperidyllpiperidine-1 -carboxylate ( 12a) _o_CNBoc 3-(4-phenoxypheny1)- 1-[ 1 -[ 1-(4-piperidy1)-4-piperidy1]-4-piperidyllpyrazolo[3,4-dipyrimidin-4-amine (2d) (0.8 g, 1.45 mmol) was dissolved Is in 20 mL of 1,2-dichloroethane, and N-tert-butoxycarbony1-4-piperidone (0.9 g, 4.51 mmol) was added, then acetic acid (0.4 g, 6.67 mmol) and anhydrous sodium sulphate (1 g) were added. Upon completion of the addition, the reaction was carried out at Date Recue/Date Received 2021-09-09 85 C for 3 h, and cooled to room temperature, sodium triacetoxyborohydride (2 g, 9.43 mmol) was added, and the mixture was reacted at room temperature overnight.
The pH was adjusted to 9-10 by adding dropwise saturated sodium bicarbonate solution, and the organic layer was dried over anhydrous sodium sulphate, then concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (DCM/Me0H (v/v) ¨ 50/1-5/1), to obtain teal-butyl 4-[4444444-amino-3 -(4-phenoxyphenyl)pyrazolo [3 ,4-djpyrimidin-l-y1]- 1-piperidy1]-1-piperidyli -1-piperidyl]piperidine-1-earboxylate (12a) (0.7 g, yield:
70%).
LCMS m/z = 736.5 [M+1] .
Step 2:
3-(4-phenoxyphenyI)-141 -[1- [1-(4-piperidyI)-4-piperi dy1]-4-piperidy1]-4-piperidyllpyrazolo [3 ,4-dl pyrimidin -4-amine (12b) =N-CN_OH

N, N
\ H2N N
N¨/
Tert-butyl 444444444-amino-3-(4 -phenoxyphenyppyrazo lo [3 ,4 -dlpyrimidin-1-y1]-1 -piperidyl] -1-pi peri dy1]-1-pi peridyllpiperidine-I-carboxylate (12a) (0.7 g, 0.95 mmol) was dissolved in 5 mL of dichloromethane, and 5 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and 20 mL of dichloromethane and 2 mL of ethanol were added, and the resulting solution was washed with saturated sodium bicarbonate solution, the aqueous phase was further extracted with 20 mL of dichloromethane and 2 mL of ethanol, and the organic layers were combined, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain 3-(4-phenoxypheny1)-1-[1-[1 4 1 -(4-piperidy1)-4.-piperidyl]-4-piperidy11-4-piperidyl]pyrazolo[3,4-d]pyrimiclin-4-amine (12b) (0.60 g, yield: 99%).
LCMS m/z = 636.3 [M+1]'.
Step 3:
Date Recue/Date Received 2021-09-09 54444- [414- [4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyri midi n- I -y1]- 1-piperidy1]-1-piperidyll -1-piperidy1]- 1-piperidy11-2-(2,6-dioxo-3 -piperidyl)isoindoline-1,3-dione pentatrifluoroacetate (compound 12) o -CN NH
0 r4----t--/c) N (NN-C-iN
N

H2N 'N
3-(4-phenoxypheny1)-1-[1-[1-[1-(4-piperidy1)-4-piperidy1]-4-piperidy11-4-piperidylipyrazol o[3,4-d]pyrimidin-4-amine (12b) (0.25 g, 0.39 1=01), 242,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (0.11 g, 0.39 mmol) and triethylamine (0.12g. 1.2 mmol) were dissolved in 3 mL of DMSO, and the mixed solution was warmed to 90 C and stirred 1.0 for 12 h. The reaction solution was cooled to room temperature, added

10 mL of water, and filtered. The filter cake was passed through Pre-HPLC (instrument and preparative column: using Glison GX-281 to prepare the liquid phase, preparative column model: Sunfire C18, 5 p.m, inner diameter x length = 30 mmx 150 mm).
Preparation method: The crude product was dissolved with methanol and dimethyl Is sulphoxide, and filtered with 0.45 pm filter membrane, to prepare into a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% TFA).
Gradient elution method: gradient elution with aeetonitrile from 5% to 60% (elution time: 15 min), the reaction system was lyophilized to obtain 54444444444-amino-3-(4-phenoxyphenyppyrazolo [3,4-d]pyrimidin-1 -y11-1-piperi dyl] -1-pi -1-20peridy1] piperidy11-1-piperidy11-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione pentatrifiuoroacetate (compound 12) (0.15 g, yield: 28%).
NMR (400 MHz, DMSO-do) 6 11.07 (s, 1H), 10.05 (br, 2H), 8.33 (s, 111), 7.75 -7.62 (m, 311), 7.48 -7.39 (m, 3H), 7.35 - 7.29 (in, 114), 7.24 - 7.10 (in, 511), 5.27 - 5.04 (1n, 3H), 5.04 - 4.35 (br, 5H), 4.30 - 4.20 (m, 2H), 3.73 - 3.43 (in, 8H), 25 3.13- 2.84(m, 6H), 2.64- 2.54(m, 2H), 2.40- 2.17(m, 614), 2.15- 1.87 (m, 71-1), 1.77 - 1.60 (in, 2H).
LCMS m/z = 892.4 [M 1].
Date Recue/Date Received 2021-09-09 Example 13:
5-[3-[4-[4-[3-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yli -1-pi peridy lj azetidin-l-y1]-1 -piperi dyl] -1 -pi peri dyll azetidi n-1-y11-2-(2,6-di oxo-3-piperidyl)isoindoline-1,3-dione (compound 13) i N
9 _O--C-IN

N, i N
---- , N --, / ________________________ ( , \ N

N=1 --,-----N_OH
0 / c) N¨/
FI,N 7AI
I 1 f N=j i N
.,..111-1 p rN -0 P g NO
0 iii ,\LN_CIN-01-`\ j sic 3 - / \ N Ni 13b 1-i2N 7 \ N Camib,und 13 Step 1:
Tert-butyl 3-[4-[4-[3-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrim idin-l-y1]-1-piperi dyl]azetidin-1 -yI]-1-pi peridy11-1-piperidyllazetidinc-1-to carboxylate (13a) 1111 _CIN N
___ON------/
N
--- 'N
/ \ N H2N
Nr------/
To a 50 mL reaction flask was successively added 3-(4-phenoxypheny1)-1-41-[1 41-(4-piperi dy1)-4-piperi dyl]az etidi n-3 - y1]-4-piperidyl]pyrazo lo [3 ,4-d]pyri rni din-4-amine (110 (420 mg, 0.69 mmol), acetic acid (41.4 mg, 0.69 mmol), tert-butyl is oxo azetidine-1-carboxylate (118 mg, 0.69 mmol), sodium triacetoxyborohydride (292.5 mg, 1.38 mmol) and dichloromethane (20 mL). Upon completion of the Date Recue/Date Received 2021-09-09 addition, the reaction was stirred at room temperature for 3 h. The reaction solution was filtered off with suction, and the filtrate was washed with saturated sodium bicarbonate solution (8 mL). The liquid separation was conducted, then the organic layer was dried over anhydrous sodium sulphate, filtered off with suction, and the filtrate was concentrated under reduced pressure, to obtain tert-butyl [4-ainino-3-(4-phenoxyphenyl)pyrazol 0[3 ,4 -d] pyrimid in- 1 -y1]-1 -piperidyl] azetid in-1 -yI]- 1 -piperidyl 1- 1 -p iperidyll azetidine- 1 -carboxyl ate (1 3a) (350 mg, yield: 67%).
Step 2:
1 -[ 1 -[ 1 -[1 -[ 1 -(azetidin-3-yl)-4-piperidyl]-4-piperidyl]azctidin-3-yl]-p iperidy1]-3-(4-phenoxyphen yl)pyrazolo[3,4-d] pyrimidin -4-am ine (1 3b) =NNJ

N
H2N \ N
N=1 Ten-butyl 3 444413 4444-am ino-3-(4- phen oxyphenyppyrazol o [3 ,4-d]pyrim id in- 1 -y11-1 piperidyl]azetid in- 1 -yI]- 1 -piperidyI]- 1 -p iperidyl]azet idine- 1 -carboxylate (13a) (350 mg, 0.46mmo1) was dissolved in 8 mL of 4 N ethyl acetate Is hydrochloride solution, and 5 mL of methanol was added, the reaction was carried out at room temperature for 2 h. The reaction solution was directly concentrated, then the reaction system was diluted with ethyl acetate (30 mL), quenched with saturated sodium bicarbonate solution (10 mL), and extracted with ethyl acetate (5 mL x 3).
The organic phase was combined, dried over anhydrous sodium sulphate, and filtered, and the filtrate was concentrated under reduced pressure, to obtain 141-[141-[1-(azeticlin-3-y1)-4-piperidy1]-4-piperidyllazetidin-3-y1]-4-piperidy1]-3 -(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine (13b) (180 mg, yield: 59%).
Step 3:
54344- [443 4444-am 4-phenoxyphenyl)pyrazo lo [3,4-d]pyrim idin-y1]- 1 -piperidyllazetidin- 1 -y11- 1 -piperidy1]-1 -piperi dyllazetidin- 1 -y11-2-(2,6-dioxo-3-piperidyl)isoindoline- 1,3-dione (compound 13) Date Recue/Date Received 2021-09-09 N

0 , N
\ H2N N
1\r"---'"
1 4 1 41 41 41-(azetidin-3-y1)-4-piperidy1]-4-piperidyflazetidin-3-y1]-4-piperidy1]-3-(4-phenoxyphenyl)pyrazolo [3,4-d] pyrimidin-4-amine ( 13b) (180 mg, 0.27 mmol) was dissolved in DMSO (20 mL), and 2-(2,6-dioxopiperidin-3-y1)-5-fiuoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (74.5 mg, 0.27 mmol) and D1PEA (174.4 mg, 1.35 mmol) were added at room temperature, the reaction was stirred at 90 C for 2 h. To the reaction solution was added 50 mL
of water, the aqueous phase was extracted with ethyl acetate (50 mL x 3), and the organic phase was combined, washed with water (20 mL x 2), dried over anhydrous sodium sulphate, and concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 100 : 1-20 : 1), to obtain a crude product. The crude product was passed through Pre-HPLC
(instrument and preparative column: using (3lison GX-281 to prepare the liquid phase, preparative column model: Sunfire C18, 5 lun, inner diameter x length = 30 11-1Mx 150 min).
Preparation method: The crude product was dissolved with methanol and dimethyl sulphoxide, and filtered with 0.45 um filter membrane, to prepare into a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% TFA).
Gradient elution method: gradient elution with acetonitrile from 5% to 60% (elution time: 15 min), the prepared product was alkalized and concentrated to obtain [4-amino-3-(4-phenoxyphenyl)pyrazolo [3 ,4-d]pyrimidin-1-y1]-1-piperidyliazetidin-1-y1]-1-piperidy1]-1-piperidyl]azetidin-1-y1]-2-(2,6-dioxo-3-piperidypisoindoline-1,3-dione (compound 13) (63 mg, yield: 25%).
111 NMR (400 MHz, CDC13) 6 8.37 (s, 111), 7.74 - 7.49 (m, 41-1), 7.43 - 7.34 (m, 211), 7.18 - 7.13 (mu, 3H), 7.09 - 7,04 (m, 2H), 6.77 (d, 1H), 6.51 (dd, 1H), 5.67 (br, 211), 5.01 - 4.88 (in, 2H), 4.34 - 4.20 (m, 114), 4.08 (t, 214), 3.90 - 3.82 (m, 214), 3.58 - 3.50 (m, 2H), 3.38 - 3.30 (m, 114), 3.13 - 3.05 (m, 114), 3.00 - 2.70 (m, 11H), 2.46 (t, 2H), 2.38 -2.29 (in, 2H), 2.19 - 2.14 (m, 214), 1.94- 1.86 (m, 6H), 1.81 -1.74 (m, Date Recue/Date Received 2021-09-09 211), 1.67-1.59 (m, 2H), 1.44 - 1.39 (m, 211), 0.99 - 0.90 (m, 211).
LCMS m/z = 460.4 [M/2 +1]+.
Example 14 54444-144444-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d[pyrimidin-1-y1]-1 -piperidy1]- 1 -piperidy 11- 1 -piperidy1]- 1 -piperi dy1]- 1 -pi peridy1]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione hexatrifluoroacetate (compound 14) -____()\---111, _CIN-ON-C
N
0-- di...,N, N-CN
1 / _______________________ 1\4 I-12N . ' \ N 6CF3COD-1 N=t"
Boc Q jalli 2 __ONO
GNI
Step I 0 ,-.0 ,N,N_U----NN-C _IN Step 2 f-i2N--C
N=i 12b 14e H
p õCy Cal p 0 Siop 3 N
,----N-r-N
.K=F3C0014 *f(isjµi Ni H2N / \ N

N¨/
14b Compound 14 Step 1:
Tert-butyl 444444414-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin- 1 -y1]-1- pi peri dy1]- 1 -piperidyl] -1 -piperidy1]- 1 -piperidyl]piperi dine- 1 -earboxylate (14a) CINBoc 9 _...-, NO¨

r--NN"-U
N
--= 'N
/ \ N H2N
N='' 3-(4-phenoxypheny1)-1-[1-[1-[1-(4-piperidy1)-4-piperidy1]-4-piperidyl[-4-Date Recue/Date Received 2021-09-09 piperidyl]pyrazolo[3,4-cl]pyrimidin-4-amine (12b) (0.3 g, 0.47 mmol) was dissolved in 20 mL of 1,2-dichloroethane, and N-tert-butoxycarbony1-4-piperidone (0.28 g, 1.42 inmol) was added, then acetic acid (0.14 g, 2.36 inmol) and 0.5 g of anhydrous sodium sulphate were added. Upon completion of the addition, the mixture was warmed to 85 C and reacted for 3 h, and cooled to room temperature. Sodium triaeetoxyborohydride (0.5 g, 2.36 minol) was added, and the mixture was reacted at room temperature overnight. The pH was adjusted to 9-10 by adding dropwise saturated sodium bicarbonate aqueous solution, and the organic layer was dried over anhydrous sodium sulphate, then concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (DCM/Me0H (v/v) 50/1-5/1), to obtain tert- butyl 4-[4- [4 - [4- [4 - [4-amino-3 -(4-phenoxyphenyl)pyrazolo [3,4-d]pyri mi din-l-y11-1-piperi dyli -1-pi peridy1]-1-piperidy11-1-piperidyl]piperidine-1-carboxylate (14a) (0.13 g, yield: 33%).
LCMS rniz = 819.5 [M+1]+.
Step 2:
3-(4-phenoxypheny1)-1-[1-[ 14 -[1-(4-p peridy1)-4-piperidyl]-4 dy11-piperidy1]-4-piperidyl] pyrazolo [3,4-dl pyrimid in-4 -amine pentatrifluoroacetate (14b) H

Tert-butyl 44444444444-amino-3 44 -phenoxyphenyl)pyrazo lo [3 ,4-d]pyrimidin-l-yli -1-piperidyli-1-piperidy1]-1-piperidy1]-1-piperidylipiperidine-1-carboxylate (14a) (0.13 2, 0.16 mmol) was dissolved in 2 mL of DCM, and 2 mL
of trifiuoroacetic acid was added. Upon completion of the addition, the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the crude product was directly used in the next step.
LCMS ¨ 719.5 [M+1r.
Step 3:
54444- [4444444 -amino-3-(4-phenoxyphenyl)pyrazolo [3,4-d]pyrimidin-1 -Date Recue/Date Received 2021-09-09 y1]-1 -piped dy1]-1 -piperidy11-1-piperi dy1]-1-piperi dy1]-1-piperidy1]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione hexatrifluoroacetate (compound 14) tit N

J-N.N
\ N. UN

H2N = N
3-(4-phenoxyphcny1)-14 I -[ 1-E1 -[1-(4-piperi dyI)-4-pip eridyI]-4 -piperidy11-4 piperidy11-4-piperi dyllpyrazolo [3,4 -d]pyrimi di n-4-ami ne pentatrifluoroacetate (14b) (0.20 g, 0.16 mmol), 2-(2,6-dioxopiperidin-3-yI)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (0.05 g, 0.17 mmol) and triethylamine (0.12 g, 1.2 mmol) were dissolved in 3 mL of DMSO, and the mixed solution was warmed to 120 C and stirred for 6 h. The reaction solution was cooled to room temperature, added 10 mL of water, and filtered. The filter cake was passed through Pre-HPLC (instrument and preparative column: using Glison GX-281 to prepare the liquid phase, preparative column model: Sunfire C18, 5 pm, inner diameter X
length = 30 mny<150 mm). Preparation method: The crude product was dissolved with methanol and dimethyl sulphoxide, and filtered with 0.45 um filter membrane, to is prepare into a sample solution. Mobile phase system: acctonitrile/water (containing 0.1% TFA). Gradient elution method: gradient elution with acetonitrile from concentration (v/v, the same below) of 5% to concentration of 60% (elution time: 15 min), the reaction system was lyophilized to obtain 5-[4-[4-[4-[4-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo [3 ,4-d]pyrimi din-l-y11-1-piperi dyll - I -pi -1-20peridy1] piperidy1]-1-piperidylj-l-piperidy1]-2-(2,6-dioxo-3-piperidypisoindoline-1,3-dione hexatrifluoroacetate (compound 14) (0.06 g, yield: 25%).
111. NMR (400 MHz, DMSO-do) 6 11.06 (s, 1H), 10.01 (br, 2H), 8.32 (s, 111), 7.74 - 7.62 (m, 311), 7.48 -7.40 (m, 3H), 7.35 - 7.28 (m, 111), 7.24 - 7.10 (m, 511), 5,24 - 4.92 (in, 3H), 4.60 - 4.17 (m, 9H), 3.75 - 3.45 (in, 11H), 3.13 -2.85 (m, 8H), 25 2.67 - 2.56 (m, 2H), 2.40 - 2.20 (m 71-1), 2.14- 1.88 (m, 8H), 1.77-1.57 (m, 211).
LCMS m/z = 975.5 [M+1]+.
Example 15:
Date Recue/Date Received 2021-09-09 54444- [344- [4-amino-344-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-l-y1]-1-piperidyllazetidin-1-y11-1-piperidy1]-1-piperidy11-2-(2,6-dioxo-3-piperidypisoindol me-1,3-dione (compound 15) =
_ON
0 rµJ--10 H2N \ N

r N
N ¨0 N kir Step I N_ __GN-N
Fi2N / H2N / \KN
=/ N=f N 1 if Compound 15 Step 1:
54444- [344-14-amino-3-(4 -phenoxyphenyl)pyrazol o[3,4 -dlpyrimidin-1 -y1]-1-pip eridy 11azetid in- I -y11-1-piperidy11-1-piperidy1]-2-(2,6-dioxo-3-piperidy0isoindoline-1,3-dione (compound 15) o 0 N
N
H2N \N
3-(4-phenoxyphenyI)-1-[1-[1 -(4-piperidy1)-4-p iperidyl] azetidin-3-y1]-4-piperidyllpyrazolo[3 ,4 -d]pyrimidin-4-amine (110 (164 mg, 0.27 mmol) was dissolved in 20 mL of DMSO, and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (74.5 mg, 0.27 mmol) and DIPEA (174.4 mg, 1.35 mmol) were added at room temperature, the reaction was stirt-ed at 90 C for 2 h. To the reaction solution was added 50 mL of water, the aqueous phase was extracted with ethyl acetate (50 nil. x 3), and the organic phase was combined, washed with water (20 triL x 2), dried over anhydrous sodium sulphate, and concentrated. The crude product was separated and purified by silica Date Recue/Date Received 2021-09-09 gel column chromatography (dichloromethane/methanol (v/v) = 100 : 1-20 : 1), to obtain a crude product. The crude product was passed through Pre-HPLC
(instrument and preparative column: using Glison GX-281 to prepare the liquid phase, preparative column model: Sunfire C18, 5 pm, inner diameter x length = 30 mm x 150 mm).
Preparation method: The crude product was dissolved with methanol and dimethyl sulphoxide, and filtered with 0.45 1..uti filter membrane, to prepare into a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% TFA).
Gradient elution method: gradient elution with acetonitrile from concentration of 5% to concentration of 60% (elution time: 15 min), the prepared product was alkalized and concentrated to obtain 54444434444-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-l-yll-1-piperidyllazetidin-l-y1]-1-piperidy1]-1-piperidy1]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dionc (compound 15) (58 mg, yield: 25%).
'H NMR (400 MHz, CDC13) 6 8.38 (s, 1H), 7.75 - 7.58 (in, 4H), 7.54 - 7.51 (m, 111), 7.40- 7.36 (in, 2H), 7.17- 7.13 (m, 3H), 7.08- 7.02 (m, 3H), 5.65 (s, 2H), 4.95 - 4.91 (m, 2H), 4.32 -4.20 (m, 1H), 3.97 (d, 214), 3.61 (s, 111), 3.53 (s, 114), 3.11 -3.10 (m, 1I1), 2.99 - 2.90 (m, 711), 2.86 - 2.85 (m, 111), 2.80 - 2.69 (in, 311), 2.60 -2.59 (m, 111), 2.49 - 2.44 (m, 1H), 2.27 - 2.14 (in, 4H), 1.95 - 1.86 (m, 6H), 1.77 -1.72 (m, 214), 1.67- 1.61(m, 2H), 0.96 - 0.94 (m, 214).
LCMS m/z = 864.5 [M+
Example 16:
5-[443- [314- [4-amino-3-(4-phenoxypheny Opyrazolo[3,4-dlpyrimidin-l-y1]- 1-piperidyllpyrrolidin-1-yllazetidin-1-y1]-1-piperidy11-2-(2,6-dioxo-3-piperidypi soindol ine-1,3-dione (compound 16) / _____________________________________________________ f N

Q N¨N

Date Recue/Date Received 2021-09-09 õCNBoc H
Q sl'-'N Sier I Q Is.1-pi step 2 0 N-N

_._ I I
0 -'= N
1-1714 N Fi2 NI' H2N
la 16a 16b õctsi.,NI3oc õ0,1_,Nli ;_....:roi_CNESoc .c..." pi Qi \ pit_P SRI, 4 Q u`,.. i \ I,.j_N... Step 5- ,----õ, 0 ----,,, 1 ,-;
H2N' N H2N N
10a 16c 166 NBoc 0 c., ..,N)1.----' 0 1) St.p C; 44,p 7 _...
' CZ N-N
Compound 16 0 ' N
I-12N N I ';

16!
Step I:
Tert-b Lay I 34444-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-l-y11-1-piperidyll pyrrolidine-l-carboxylate (16a) NõCp NN acic Q
¨r- \
/
i To a 50 mL reaction flask was successively added 3-(4-phenoxypheny1)-1-(piperidin-4-y1)-1H-pyrazol o[3,4-dipyrimidin-4-amine (1a) (see J. Med. Chem.
2015, 58, 9625-9638 for the synthetic method) (1.16 g, 3 mmol), acetic acid (180 mg, mmol), tert-butyl 3-oxo-pyrrolidine- I -carboxylate (555.7 mg, 3 mmol), sodium triacetoxyborohydride (953.7 mg, 4.5 mmol) and diehloromethane (40 mL). Upon completion of the addition, the reaction was stirred at room temperature for 3 It The reaction solution was filtered off with suction, and the filtrate was washed with Date Recue/Date Received 2021-09-09 saturated sodium bicarbonate solution (30 mL). The liquid separation was conducted, then the organic layer was dried over anhydrous sodium sulphate, filtered off with suction, and the filtrate was concentrated under reduced pressure, to obtain tert-butyl 34444-amino-3-(4-phenoxyphenyl )pyrazolo[3,4-djpyrimidin-l-y1,1-1 piperidyl]pyrrolidine- 1 -carboxylate (16a) ( L2 g, yield: 72%).
Step 2:
3-(4-phenoxypheny1)-1-( I -pyrroli din-3-y1-4-piperidyl)pyrazolo [3,4-b]pyri din-4-amine (16b) õONFI
Q NNQ

Tert-butyl 3-[444-amino-3-(4-phenoxyphenyl)pyrazolo [3,4-d]pyrimidin-l-y11-1-piperidyllpyrrolidin -1 -carboxylate (16a) (1.1 g, 2 mmol) was dissolved in 10 mL
of 4 N ethyl acetate hydrochloride solution, and 5 mL of methanol was added, the reaction was carried out at room temperature for 2 h. The reaction solution was directly concentrated, then the reaction system was diluted with ethyl acetate (30 mL), quenched with saturated sodium bicarbonate (10 mL), and extracted with ethyl acetate (5 mL 3). The organic phase was combined, dried over anhydrous sodium sulphate, and filtered, and the filtrate was concentrated under reduced pressure, to obtain 3-(4-phenoxypheny1)-1- (1-pyrro lid in-3 -y1-4 -pipe ridOpyrazo lo [3 ,4-bjpyridin-4-amine (16b) (837 mg, yield: 92%).
Step 3:
Tert-butyl 3 -[3- [4-[4-amino-3 -(4-phenoxyphenyl)pyrazolo [3 ,4-d]pyri midin-yl] -pi peridyli pyn-o lid in-1- yl] azeti di ne-l-carboxylate (16c) ,C=-1)1 Boc Q N¨N

I ) Date Recue/Date Received 2021-09-09 To a 50 mL reaction flask was successively added 3-(4-phenoxypheny1)-1-(1-pyrrolidin-3-y1-4-piperidyl)pyrazolo[3,4-blpyridin-4-amine (16b) (837 mg, 1.84 mmol), acetic acid (110.4 mg, 1.84 mmol), tert-butyl 3-oxo azetidine- 1 -carboxylate (315 mg, 1.84 mmol), sodium triacetoxyborohydride (924 mg, 4.36 mmol) and dichloromethane (40 rnL). Upon completion of the addition, the reaction was stirred at room temperature for 3 h. The reaction solution was filtered off with suction, and the filtrate was washed with saturated sodium bicarbonate solution (20 mL).
The liquid separation was conducted, then the organic layer was dried over anhydrous sodium sulphate, filtered off with suction, and the filtrate was concentrated under reduced pressure, to obtain tert-butyl 3434444-amino-3-(4-phenoxyphenyl)pyrazolo [3,4 -d]pyrimid in-1 -y11-1 -piperidyli pyrrolid in-1 -yl] azetidinc-l-carboxylatc (16c) (680 mg, yield: 61%).
LCMS m/z = 611.4 [M-F-1-1+.
Step 4:
14111-(azetidin-3-yl)pyrrol idi n-3 -y11-4-piperidy11-3 -(4-phenoxypheny I )pyrazolo [3 ,4 -d] pyrimidin-4-am ne (16d) NH
NP
Qu--Tert-butyl 3 434444 -ami no -3 -(4-phenoxyph enyl)pyrazolo [3 ,4 -d]pyrimid i n-1-y1]-1-piperidyl]pyn-o I id in-l-yl]azetid ine-l-carboxylate (16c) (680 mg, 1.11 mmol) was dissolved in 8 mL of 4 N ethyl acetate hydrochloride solution, and 5 mL of methanol was added, the reaction was carried out at room temperature for 2 h.
The reaction solution was directly concentrated, then the reaction system was diluted with ethyl acetate (30 mL), quenched with saturated sodium bicarbonate (10 mL), and extracted with ethyl acetate (5 mL x 3). The organic phase was combined, dried over anhydrous sodium sulphate, and filtered, and the filtrate was concentrated under reduced pressure, to obtain 1 -[1- [1-(azetidin-3-yl)pyrrolidin-3-y1]-4-piperidy1]-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine (16d) (420 mg, yield: 74%).
Date Recue/Date Received 2021-09-09 Step 5:
Tert-butyl 443434444- amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-y1]-1-piperidyl] pyrrolidi azetidin-1 -yl] piperidine-l-carboxy late (16e) NBoc NNJ
fia To a 50 mL reaction flask was successively added 141 41-(azetidin-3-yppyrrol id i n-3-yI]-4-piperidyl] -3-(4-phenoxyphenyl)pyrazol o[3,4 -dipyrimi din-4-amine ( I 6d) (420 mg, 0.82 mmol), acetic acid (49.2 mg, 0.82 mmol), tert-butyl 4-oxopiperidine- 1 -carboxylate (163.4 mg, 0.82 mmol), sodium triacetoxyborohydride (348 mg, 1.64 mmol) and dichloromethane (35 mL). Upon completion of the addition, the reaction was stirred at room temperature for 3 h. The reaction solution was filtered off with suction, and the filtrate was washed with saturated sodium bicarbonate solution (15 mL). The liquid separation was conducted, then the organic layer was dried over anhydrous sodium sulphate, filtered off with suction, and the filtrate was concentrated under reduced pressure, to obtain tert-butyl 4431344-1-4-amino-3-(4-is phenoxyphenyl)pyrazolo [3,4-d]pyrimid in-1-y1]-1 -piperidyl]pyrrolid in-i..
yl]azetidin-l-ylipiperidinc-1-carboxylate (1 6e) (320 mg, yield: 56%).
Step 6:
3-(4-phenoxyphenyI)-1-[ I -[ I - [1-(4-piperidyl)azetidin-3-yl]pyrrol id in-3-y1]-4-piperidyl]pyrazolo [3 ,4 -d] pyrimidin-4-amine (161) NNli CZ NN

Tert-butyl 4 -[3-[3 -[4-[4-amino-3-(4 -phenoxyphenyl)pyrazolo [3 ,4-d]pyrimidin-l-y1]-1-piperidyl]pynolidin-l-yl] azetidin-1 -yl] piperidine-l-carboxylate (16e) (320 mg, 0.46 mmol) was dissolved in 8 mL of 4 N ethyl acetate hydrochloride solution, Date Recue/Date Received 2021-09-09 and 5 mL of methanol was added, the reaction was carried out at room temperature for 2 h. The reaction solution was directly concentrated, then the reaction system was diluted with ethyl acetate (30 mL), quenched with saturated sodium bicarbonate (10 mL), and extracted with ethyl acetate (5 mL x 3). The organic phase was combined, dried over anhydrous sodium sulphate, and filtered, and the filtrate was concentrated under reduced pressure, to obtain 3-(4-phenoxypheny1)-1414111-(4-piperidypazetidin-3 -yljpyrroli din-3 -y1]-4-piperidyl]pyrazo lo [3 ,4-d]pyrimi din-4-amine (160 (210 mg, yield: 77%).
Step 7:
544- [343-[444-amino-3-(4-phenoxyphenyppyrazol o[3,4-d]pyri midi n- I -y1]- I -piperidyl]pyrrolidin-l-yl] azetidin-l-y11-1-piperidy11-2-(2,6-dioxo-3-piperidypi soindoline-1,3-di one (compound 16) Q, Q N

) 3-(4-phenoxypheny1)-1-[1-[1- [1 -(4-piperidyl) azetidin-3-yljpytTolidin-3-y1]-piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (161) (210 mg, 0.35 mmol) was dissolved in DMSO (20 mL), and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (96.7 mg, 0.35 mmol) and D1PEA (174.4 mg, 1.35 mmol) were added at room temperature, the reaction was stirred at 90 C for 2 h. To the reaction solution was added 50 mL of water, and the layers were separated. The aqueous phase was extracted with ethyl acetate (50 mL
3), and the organic phase was combined, washed with water (20 mL x 2), dried over anhydrous sodium sulphate, and concentrated. The crude product was separated and purified by silica gel column chromatography (dichlorornethane/methanol (v/v) =
100: 1-20: 1), to obtain a crude product. The crude product was passed through Pre-HPLC (instrument and preparative column: using Glison GX-281 to prepare the liquid phase, preparative column model: Sunfire C18, 5 um, inner diameter x length Date Recue/Date Received 2021-09-09 = 30 mmx 1 50 mm). Preparation method: The crude product was dissolved with methanol and dimethyl sulphoxide, and filtered with 0.45 pm filter membrane, to prepare into a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% TFA). Gradient elution method: gradient elution with acetonitrile from concentration of 5% to concentration of 60% (elution time: 15 min), the prepared product was alkalized and concentrated to obtain 54443434444-arnino-3-(4-phenoxyphenyppyrazolo[3,4-d]pyrimidin-l-yli-l-piperidyllpyrrolidin-l-yll azetidin-l-y11-1-piperidyli-2-(2,6-dioxo-3-piperidypisoindo line-1,3-di one (compound 16) (58 mg, yield: 32%).
H NMR (400 MHz, CDC13) 6 8.38 (s, 111), 7.75 - 7.50 (m, 4H), 7.42 - 7.35 (m, 214), 7.256-7.25(m, 1H), 7.19 - 7.10 (m, 3H), 7.08-7.06 (m, 2H), 7.04 - 6.98 (m, 1H), 5.72 (s, 2H), 5.00-4.90(m, 211), 4.67 (s, 2H), 4.38 - 4.18 (in, 114), 3.86 -3.74 (m, 214), 3.47-3.42 (m, 211), 3.13 - 2.98 (m, 614), 2.90 - 2.64 (in, 6H), 2.45-2.43 (m, 111), 2.37 - 2.32 (in, 211), 2.19 - 2.10 (m, 5H), 2.05-2.03 (m, 211), 1.81 - 1.77 (m, 2H), 0.98-0.90 (m, 2H).
LCMS m/z = 425.8 [M/2 +1].
Example 17:
5-[3-[3- [4-[4-amino-3 -(4-phenoxyphenyl)pyrazolo [3 ,4-d]pyrimid piperidyl]azetidin-1 -y dazetidin-1 -y11-2-(2,6-d ioxo-3-p iperidypisoindoline-1,3-dione (compound 17) 0 o NNr\No Date Recue/Date Received 2021-09-09 (,) 0 /...,,,Boc SteP2 N,N...CNH N _CiN-. Y ,N.N_Cr N
142N / \N H2N / \N
H2N / 'N
Kl=f la 170 17b Step :1 0 ,___,C,N
Swp4 , 0 F.I2N / \N 112N / 1,4 N=I
17c 17d --- , N
/ \
H2N N Compound 17 N=1'.
Step 1:
tert-butyl 344-[4-amino-3-(4-phenoxyphenyppyrazolo [3,4-d]pyrimidin-l-yli-l-piperidyflazetidine-1-earboxylate (17a) N- B c N=
3-(4-phenoxypheny1)-1-(piper id in-4-y1)-1H-pyrazolo [3,4-djpyr imidin-4-am ine (la) (see J. Med. Chem. 2015, 58, 9625-9638 for the synthetic method) (0.500g.
1.29 minol) was dissolved in 5 inL of 1,2-dichloroethane, and tert-butyl 3-oxoazetidine-1-carboxylate (0.266 g, 1.55 mrnol) and glacial acetic acid (0.412 g, 6.86 rnmol) were successively added. Upon completion of the addition, the reaction was carried out at 65 C for 3 h. The reaction solution was cooled to room temperature, and sodium triacetoxyborohydride (0.548 g, 2.59 mmol) was added. Upon completion of the addition, the reaction was carried out at room temperature overnight. To the reaction solution was added dropwise saturated sodium bicarbonate solution to adjust the pH
to 9-10, and same was concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography Date Recue/Date Received 2021-09-09 (dichloromethane/methanol (v/v) = 100 : 0-19: 1), to obtain tert-butyl 3-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-l-y11-1-piperidyliazetidine-1-carboxylate (17a) (0.700 g, yield: >99%).
LCMS m/z = 542.3 [M+1] .
Step 2:
141-(azetidin-3-y1)-4-piperidy1]-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine (17b) .N-C/NH
H2N 'N
N=--/
Tert-butyl 34444- amino-3 -(4-phenoxyphenyl)pyrazolo [3,4-djpyrimidin-l-y1]-1-piperidyliazetidine- 1 -carboxylate (17a) (0.700 g, 1.29 mmol) was dissolved in 2 mL of dichloromethane, and 5 mL of 4 N ethyl acetate hydrochloride solution was added, the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, and then to the residue was added 20 mL
of dichloromethane. The p1-1 was adjusted to 9-10 with saturated sodium bicarbonate solution. The liquid separation was conducted, and the organic layer was dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain (azeti din-3-y1)-4-piperidy11-3-(4-phenoxyphenyl )pyrazolo [3,4-di pyrim idi n-4-am i ne (17b) (0.410g. yield: 72%).
LCMS m/z = 442.2 [M+1]1.
Step 3:
tert-butyl 3 -[3-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo [3 ,4-d]pyrimidin-1-yl] -1-pi peridyl] azet id in-l-yl] azet idin e-l-carboxylate (17c) N. C
N iN
¨
H2N \ N
N=i -[1-(azet idin -3-y1)-4-piperidyl] -3 -(4-phenoxyph enyl)pyrazol o [3,4-Date Recue/Date Received 2021-09-09 d]pyrimidin-4-amine (17b) (0.200 g, 0.453 mmol) was dissolved in 5 mL of 1,2-dichloroethane, and tert-butyl 3-oxoazetidine- 1 -carboxylate (0.116 g, 0.680 mmol) and glacial acetic acid (0.0544 g, 0.906 minol) were successively added. Upon completion of the addition, the reaction was carried out at 65 C for 3 h. The reaction solution was cooled to room temperature, and sodium triacetoxyborohydride (0.192 g, 0.906 mmol) was added. Upon completion of the addition, the reaction was carried out at room temperature overnight. The pH was adjusted to 9-10 by adding dropwise saturated sodium bicarbonate solution to the reaction solution. The reaction solution was concentrated under reduced pressure, and then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) ,---- 100 : 0-19 : 1), to obtain tert-butyl 3434444-amin 0-344-phenoxyphenyl)pyrazolo [3,4-d]pyrimidin-l-y11-1-p iperidyli azetidin-l-yliazet idine-1 -carboxylate (17c) (0.150 g, yield: 56%).
LCMS m/z = 597.3 [M+1]+.
Step 4:
1-[l -[1-(azetid in-3 -ypazetid in-3 -y1]-4-p iperidy1]-3-(4-phenoxyphenyl )pyrazolo [3,4 -d]pyrimidin-4-am inc (17d) ON _GN
I-12N \ N
N
Tert-butyl 3 434444-amino-3-(4-phenoxyphenyl)pyrazolo [3,4-d]pyrimidin-1-yli -1-piperidyl]azetidin-l-yl]azetidine-l-carboxylate (17e) (0.140 g, 0.235 mmol) was dissolved in 2 mL of dichloromethane, and 5 mL of 4 N ethyl acetate hydrochloride solution was added, the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, and then to the residue was added 20 mL of dichloromethane. The pH was adjusted to 9-10 with saturated sodium bicarbonate solution. The liquid separation was conducted, and the organic layer was dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain 1-[1-[1-(azetidi n-3 -yl)azeti din-3 -yl] -4-piperi dy1]-3 -(4 -Date Recue/Date Received 2021-09-09 phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine (17d) (0.100 g, yield: 86%).
LCMS m/z = 497.3 [M4-1]+.
Step 5:
5-13-13-1,444-amino-3-(4-phenoxyphenyl)pyrazolo [3 ,4-d jpyrim id in -1-y11-1 -p iperidyl ]azetidin-1 -y l]azetidin-1 -y11-2-(2,6-dioxo-3-p iperidyl)isoindol in e-1,3-dion e (compound 17) o 0 N--tt H2N / \N
141 41-(azetid in-3 -ypazetid in-3 -y1]-4-piperidy11-3-(4-phenoxyphenyl)pyrazolo[3,4-djpyrirnidin-4-amine (17d) (ft 100 g, 0.201 mmol) was dissolved in 2 nal,. of dimethyl sulphoxide, and 242,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (0.0667 g, 0.242 mmol) and diisopropylethylamine (0.130 g, 1.01 mmol) were successively added. Upon completion of the addition, the reaction was carried out at 90 C
for 2 h.
The reaction solution was cooled to room temperature, to which 10 triL of water was is slowly added dropwise, and filtered. The filter cake was dissolved with 20 rnL of dichloromethane, and then washed with 5 mL of saturated sodium chloride solution.
The liquid separation was conducted, and the organic layer was dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 100 : 0-19 : 1), to obtain 5-[3434444-amino-(4-phenoxyphenyl)pyrazolo [3,4 -d]pyrimidin-1-y1]-1-piperidyl] azetidin-1-yl] azeti din-1 -y1]-2-(2,6-dioxo-3 -p iperi dyl) isoindol ine -1,3 -dionc (compound 17) (0.063 g, yield: 42%).
1H NMR (400 MHz, CDC13) ö 9.99 (s, 1H), 8.39 (s, 1H), 7.72 - 7.57 (m, 3H), 7.45 - 7.32 (in, 2H), 7.21 -7.11 (m, 31-1), 7.10- 7.04 (m, 21-1), 6.78 (d, 111), 6.52 (dd, 111), 5.81 (brs, 2H), 4.92 (dd, 11-1), 4.87 - 4.71 (m, 1H), 4.08 - 3.99 (in, 2H), 3.94 -3.83 (in, 2H), 3.76 - 3.65 (in, 1H), 3.64 - 3.49 (m, 2H), 3.20 - 3.04 (m, 3H), 3.00 -Date Recue/Date Received 2021-09-09 2.64 (m, 511), 2.52 - 2.34 (m, 211), 2.18 - 1.89 (m, 511).
LCMS m/z = 377.3 [M/2 +1].
Example 17-1:
54343-14-14-amino-3-(4-phenoxyphenyl)pyrazolo13,4-dipyrimidin-1-y11-1 piperidyljazetidin-1-yl]azetidin-l-y11-2-[(3R)-2,6-dioxo-3-piperidyl]isoindoline-1,3-dione (compound 17-a) 54343- [444-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-djpyrimidin-l-y1]-1-piperidyljazetidin-1-yljazetidin-1-y11-2-1(3S)2,6-dioxo-3-piperidyflisoindoline-1,3-dione (compound 17-b) 414 Nõ.-14; N R) NH

N
\ N H2N
N=

N

N
\ H2N N
N=1 (9 PNNH

,N,tro / \N
N=J
Slei) )4'NO 0 1.42NN
N=.1 NH
Compocmd 17 n uiN

Step 1: Preparation of compounds 17-a and 17-b Compounds 17-a and 17-b were separated and prepared from compound 17 by is means of high performance liquid chromatography. The preparation conditions were as follows:
Date Recue/Date Received 2021-09-09 instrument and preparative column: using Thar 200 preparative SFC (SFC-7) to prepare the liquid phase, preparative column model: ChiralCel 03, 250 x 50 mm pin.
Preparation method: the crude product was dissolved with 5 methanol/dichloromethane, to prepare into a sample solution.
Mobile phase system: sCO2 (supercritical CO2)/ethanol, isocratic elution:
sCO2/ethanol = 55/45.
Flow rate: 200 mL/min Analysis method for compounds 17-a and 17-b:
10 Instrument: Agilent HPLC1260 Chromatographic column: Daicel CHIRALPAK IC
Specification: 4.6 mm 250 mm, 5 urn Mobile phase A: 20 mM of ammonium bicarbonate solution (adjusting pH to 9.0 with diethylamine) Mobile phase B: Acetonitrile Column temperature: 35 C
Flow rate: 0.8 mL/min Wavelength: 264 nm Elution program: mobile phase A: B = 20: 80, equal elution for 50 min.
Retention time of compound 17-a: 32.234 min;
111 NMR (400 MHz, CDC13) 6 9.04 (s, 111), 8.38 (s, 1H), 7.69 - 7.60 (m, 3H), 7.42- 7.34 (m, 2H), 7.21 - 7.11 (in, 3H), 7.11 - 7.05 (in, 2H), 6.78 (11, I
H), 6.52 (dd, 1H), 5.63 (brs, 2H), 4.92 (dd, 1H), 4.85 -4.72 (m, IH), 4.09 - 3.98 (m, 2H), 3.93 -3.82 (m, 2H), 3.74 - 3.64 (m, IH), 3.61 - 3.50 (in, 2H), 3.16 - 3.01 (m, 3H), 2.99 -2.64 (in, 5H), 2.52 - 2.34 (m, 2H), 2.17 - 1.95 (in, 5H).
Retention time of compound 17-b: 36.797 min. 'El NMR (400 MHz, CDC13) 6 8.37 (s, 1 fi), 7.68 - 7.57 (m, 3H), 7.43 - 7.33 (in, 2H), 7.20 - 7.10 (m, 3H), 7.10 - 7.04 (m, 2H), 6.78 (d, 1H), 6.52 (dd, 1H), 5.71 (brs, 2H), 4.92 (dd, 1H), 4.84 -4.72 (m, 1H), 4.08 - 3.98 (m, 2H), 3.91 - 3.82 (in, 2H), 3.76 - 3.64 (in, tH), 3.60 -3.50 (m, 21-1), 3.16 - 3.01 (in, 3H), 2.98 - 2.62 (m, 5H), 2.51 - 2.34 (m, 2H), 2.17 -1.97 (m, 5H).
Date Recue/Date Received 2021-09-09 Example 17-a 54343- [4- [4-amino-3-(4-phenoxyphenyl)pyrazolo [3,4- ci]pyrimid in-1-y11-1-p iperidy ljazetidin-l-y ljazetidin-1-y1]-2-[(3R)-2,6-dioxo-3-piperidy ljisoindoline-1,3-dione (compound l 7-a) pN

4 H2N _______________________ S IT-=/

['NH Q __(--,VOMe 0 _(/ NI .---OIVI
---N-----1 Step i r-N
- N - 0 4 IN.NrCiN- "( 0 Step 2 ..
H2N / \ N
N¨/ 17d H21\1¨</ \'N
N¨/ 17e I. i OH 0 ....t.7 OH
0 0 PNI--CiN -- IN 0 'N.N_CIN -I 0 - -yup , . .. _,... 0 .,NNGINI-H2N / \ N H2N4 N¨' 17f N¨/ compound 17-a Step 1:
Dimethyl 4-(3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-1-yDpiperidin-l-y1H1 ,3'-biazetidin ]-1'-yl)phtha late (17e) Ili N et CO2Mc .,..N---- CO2Me N, 0 " N
/ \N H2N
N=
1-[11-[l -(azetidin-3-ypazetidin-3-y1]-4-piperidy11-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrirnidin-4-amine (17d) (83 g, 0.167 mol) was dissolved in 400 m L of DMSO, and dimethyl 4-fluorophthalate (40g. 0.188 mol) (see Beilstein J. Org. Chem. 2017, 13, 2659-2662 for the synthetic method) and DIPEA
(43.17 g, 0.334 mol) were added, the reaction was stirred at 85 C for 5 h. The reaction solution was cooled to room temperature, and by addition of 4 L of water, a yellow Date Recue/Date Received 2021-09-09 solid was precipitated, which was filtered off with suction and dried, to obtain the crude product 4-(3- (4-(4-amino-3 -(4-phenoxypheny1)-11-1-pyrazo lo [3 ,4-d]pyrimidin-1-y Opiperidin-1-y1)[1 ,3'-b1 azetidin]-1'-y Ophilialate (17e) (120 g).
LC-MS m/z = 689.3 [M+ I r.
Step 2:
4-(3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-d]pyri mi di n-1-yppiperidin- 1-y1)41,31-bi azeti din]-11- yl)phthalic acid (170 OH
N, 0 N
\ H2N N
The above crude product 4-(3- (4-(4-amino-3- (4-phenoxyphenyI)-1H-pyrazo lo [3 ,4-d]pyrimi din-l-yl)piperidi n-l-y1)[1,3'-biazetidin]-1'-yl)phthalate (17e) (120 g) was dissolved in 400 rnL of 1,4-dioxane, and 300 mL of methanol and inL of 5 mol/L sodium hydroxide solution were added, and the reaction was stirred at 75 C for 1 h. The reaction solution was cooled to room temperature, and concentrated under reduced pressure to remove most of methanol and 1,4-dioxane, is the remaining was added I L of water, and extracted with 1 L of the mixed solvent of dichloromethane/methanol (v/v) = 9: 1. The aqueous phase was separated (adjusting the pH of the aqueous phase to 5.0 with acetic acid), and then extracted with 1 L of the mixed solvent of dichloromethane/methanol (v/v) The organic phase was separated, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, to obtain the crude product 4-(3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo [3 ,4-d]pyrimidin-1-Apiperidin-1 -y1)-[1,3'-biazetidin]-1 r-y0phthal ic acid (170 (93 g).
LCMS m/z = 66L3 [M+1]+.
Step 3:
5 -[3 -[3- [4-[4-amino-3-(4-phenoxyphenyl)pyrazolo [3 ,4-d]pyrimid in-1-yl] -1-piperidyl]azetidin- I -yl]azetidin- I -y1]-2-[(3R)-2,6-dioxo-3-piperidyl] soin dol in e-1,3-dione (compound 17-a) Date Recue/Date Received 2021-09-09 N

N

N:=2 The above crude product 4-(3 -(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazo lo [3 ,4-d]pyrirnidin-l-y 1)piperidin-l-y1)-[1,3'-biazetidir]-lt-y1)phthalic acid (170 (40.0 g) was dissolved in 200 inL N,N-dimethylformamide, and N-s methylimidazole (7.20 g, 87.7 mmol) was added, then tetramethylchlorourea hexafluorophosphate (20.0 g, 71.3 mmol) was added, the mixture was stirred at room temperature for 30 min, added 200 mL of anhydrous methanol, and stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the residue was added 500 mL of water and slurried for 1 h, and filtered off with suction under reduced pressure. The filter cake was washed with 100 mL of water once, collected and dried, to obtain a crude product (40 g). The crude product (28.0 g) was dissolved in 175 mL of N,N-dimethylformamide, and diisopropylethylamine (8.03 g, 62.1 mmol) was added, then HATU (18.9 g, 49.7 mmol) was added. The mixture was stirred at room temperature for 30 min, and (R)-3-aminopiperidine-2,6-is hydrochloride (8.90 g, 54.1 mmol) (see Heterocycles 2015, 91, 764-781 for the synthetic method) and diisopropylethylamine (8.03 g, 62.1 mmol) were successively added, and the stirring was continued at room temperature for 30 min. The reaction solution was slowly added dropwise to 700 mL of water with stirring, and filtered off with suction under reduced pressure. The filter cake was washed with 50 mL of water, collected, dissolved with 300 mL of the mixed solvent of methanol and dichloromethane (v/v) = 1 : 9, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then to the residue was added 350 mL of diehloromethanc and diisopropylethylamine (8.03 g, 62.1 mmol), and the mixture was stirred at room temperature for 18 h. To the reaction solution was added 100 mL
of water and 100 mL of dichloromethane. The liquid separation was conducted, and the organic layer was washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then Date Recue/Date Received 2021-09-09 the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 100 : 0-93 : 7), to obtain 543434444-amino-3-(4-phenoxyphenyl)pyrazolo [3,4-d]pyrimidin-l-yli- 1-piperidyl]azetidiii- 1-yl jazetidi n-1-y1]-2-[(3R)-2,6-di oxo-3-piperidyl jisoindol inc-1,3-di one (compound 17-a) (16.0 g, three-step yield calculated from compound 17d: 42%, cc = 96%).

11-1 NMR (400 MHz, CDC13) 6 9.04 (s, 1H), 8.38 (s, 1H), 7.69 - 7.60 (m, 3H), 7.42- 7.34(m, 2H), 7.21 - 7.11 (m, 3H), 7.11 - 7.05 (m, 2H), 6.78 (d, 1H), 6.52 (dd, 11-1), 5.63 (brs, 2H), 4.92 (dd, 1H), 4.85 - 4.72 (n, 1H), 4.09 - 3.98 (m, 2H), 3.93 -3.82 (m, 211), 3.74 - 3.64 (in, 111), 3.61 - 3.50 (m, 211), 3.16 - 3.01 (m, 311), 2.99 -2.64 (in, 5H), 2.52 - 2.34 (in, 2H), 2.17 - 1.95 (n, 5H).
LCMS m/z = 753.3 [M+1]
Example 17-b 54343- [444-amino-3-(4-phenoxyphenyppyrazolo [3,4-d]pyrimid in-1-y11-1 -piperidyljazetid in-1 -yljazetid in-1 -yI]-2-[(3S)-2,6-d ioxo-3-p iperidyl]
isoindoline-1 ,3-dione (compound 17-b) \ H2N N
N=-/

Q
NH All OMe OMR
N Step 2 N¨/ 17d H2N \ N
N= 17e \ OH is N-t710 0, I-12N 17-b Compound N=7 17f N=
Step 1:
Dimethyl 4-(3 -(4-(4-amino-3 -(4-phenoxyphenyl)-1H-pyrazo lo [3,4-Date Recue/Date Received 2021-09-09 d]pyrimidin-l-yOpiperidin-1-y1)41,3'-biazetidini-l'-yOphthalate (17e) co,me o-N-CO2Me I-12N);
141 41- (azeti din-3-y!) azeti din -3-yI]-4-piperi dyli -344-phenoxyphenyppyrazolo[3,4-djpyrimidin-4-amine (17d) (83 g, 0.167 mol) was dissolved in 400 mL of DMSO, and dimethyl 4-fluorophthalate (40g. 0.188 mol) (see Beilsteth I Org. Chem. 2017, 13, 2659-2662 for the synthetic method) and D1PEA

(43.17 g, 0.334 rnol) were added, the reaction was stirred at 85 C for 5 h.
The reaction solution was cooled to room temperature, and by addition of 4 L of water, a yellow solid was precipitated, which was suction-filtered and dried, to obtain the crude product 4-(3 -(4- (4-amino-3-(4-phenoxyphcny1)-1H-pyrazolo [3 ,4-d]pyrimidin-1-yl)piperidin- 1 -y1) [1,3'-biazetidi n]-1'-yl)phthal ate (17e) (120 g).
LC-MS in/z = 689.3 [M+1 r.
Step 2:
4-(3-(4- (4-amino-3- (4-phenoxypheny0-1H-pyrazolo [3,4-d]pyrimi di n-1 -yl)piperidin-l-y1)41,3'-biazetidinj-11-ypphthalic acid (170 OH
OH

/

The above crude product 443-(4-(4-amino-3- (4-phenoxypheny1)-11-1-pyrazo lo [3 ,4-d}pyrimidi n-l-yl)pi peridi n-l-y1)[1,3t-biazetidi ni-lt-yl)phthalate (17e) (120 g) was dissolved in 400 mL of 1,4-dioxane, and 300 inL of methanol and mL of 5 mol/L sodium hydroxide solution were added, and the reaction was stirred at 75 C for 1 h. The reaction solution was cooled to room temperature, and concentrated under reduced pressure to remove most of methanol and 1,4-dioxane, the remaining was added 1 L of water, and extracted with 1 L of the mixed solvent of Date Recue/Date Received 2021-09-09 dichloromethane/methanol (v/v) = 9: 1. The aqueous phase was separated (adjusting the p1-1 of the aqueous phase to 5.0 with acetic acid), and then extracted with 1 L of the mixed solvent of dichloromethane/methanol (v/v) ¨9 : 1. The organic phase was separated, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, to obtain the crude product 4-(3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-l-y1)piperidin-l-y1)41,3'-biazetidin]-11-y1)phtlialic acid (170 (93 g).
LCMS m/z = 661.3 [M+1] .
Step 3:
54343- [444-amino-3-(4-phenoxypheny Opyrazolo [3 ,4-d]pyrim id in -1-y1]- I -p iperidyl azetidi n-1 -y 11 azetid in-1 -y11-2-[(3S)-2,6-d ioxo-3-piperidyli isoindoline-1,3-dione (compound 17-b) N, N

N=1 The above crude product 4-(3-(4-(4-amino-3-(4-phenoxyphenyI)-1H-pyrazo lo [3 ,4-d]pyrimidin-1-y Opiperidin-l-y1)-[1,3'-biazetidin]-1`-yl)phthalic acid (170 (40.0 g) was dissolved in 200 mL N,N-dimethylformamide, and N-methylimidazole (7.20 g, 87.7 mmol) was added, then tetramethylchlorourea hexafluorophosphate (20.0 g, 71.3 mmol) was added, the mixture was stirred at room temperature for 30 min, added 200 mL of anhydrous methanol, and stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the residue was added 500 mL of water and slurried for 1 h, and filtered off with suction under reduced pressure. The filter cake was washed with 100 mL of water once, collected and dried, to obtain a crude product (40 g). The crude product (40.0 g) was dissolved in 200 mL of N,N-dimethylformamide, and diisopropylethylamine (11.5 g, 89.0 mmol) was added, then HATU (27.0 g, 71.0 mmol) was added. The mixture was stirred at room temperature for 30 min. and (S)-3-aminopiperidine-2,6-dione hydrochloride (12.7 g, 77.2 mmol) (see Heterocycles 2015, 91, 764-781 for the Date Recue/Date Received 2021-09-09 synthetic method) and diisopropylethylamine (11.5 g, 89.0 mmol) were successively added, and the stirring was continued at room temperature for 30 min. The reaction solution was slowly added dropwise to 800 mL of water with stirring, and filtered off with suction under reduced pressure. The filter cake was washed with 100 mL of water, collected, dissolved with 600 mL of the mixed solvent of methanol and diehloromethane (v/v) ¨ I : 9, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then to the residue was added 400 mL of dichloromethane and diisopropylethylamine (11.5 g, 89.0 mmol), and the mixture was stirred at room temperature for 18 h. To the reaction solution was added 100 mL
of water and 100 mL of dichloromethane. The liquid separation was conducted, and the organic layer was washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 100 0-93 7), to obtain 5-[3-[3-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo [3,4-d1pyri midin-1-y1]-1-piperidyllazetidin- 1-yflazetidin- 1-y11-2-[(3S)-2,6-dioxo-3-piperidyflisoindol ine- 1,3-d ione (compound 17-b) (20.0 g, three-step yield calculated from compound 17d: 37%, ee = 93%).
1H NMR (400 MHz, CDC13) 6 8.37 (s, 1H), 7.68 - 7.57 (m, 3H), 7.43 - 7.33 (m, 2H), 7.20 - 7.10 (m, 3H), 7.10 - 7.04 (m, 2H), 6.78 (d, 1H), 6.52 (dd, 1H), 5.71 (brs, 2H), 4.92 (dd, 1H), 4.84 - 4.72 (m, 1H), 4.08 -3.98 (m, 2H), 3.91 -3.82 (m, 2H), 3.76 -3.64 (m, 1H), 3.60 - 3.50 (m, 2H), 3.16 - 3.01 (m, 3H), 2.98- 2.62 (m, 5H), 2.51 -2.34 (m, 2H), 2.17 - 1.97 (in, 5H).
LCMS m/z = 753.3 [M+1].
Example 18:
cis-5 -(3-(4-(4-amino-3-(4-phenoxyphenyt)-1H-pyrazolo [3,4-d] pyri mi din-l-y1)-l'-yl)azetidin-l-y1)-2-(2,6-dioxopiperid in-3-yl)isoindoline-1,3-dione tri fluoroacetate (compound 18) Date Recue/Date Received 2021-09-09 H2N \ z N
fa N._..r \II () 0 NH

N

N--'-"\ N.-, \
H2N \ , NI N

H2N \ , N
¨2¨r4 \ / N
Step 1 Step 2 \N -N ¨11.- ,N F
o_.&
H
0- 0 \N n_ . .
OH
--..1 N
----` (cis) ------cis) 1 a o 18a 18b N. Boo a N- \N

Sul, 3 Slert-t Step 5 _ y - - , '=- N c...IN j__ F ______________________________________ Y"- = N , -a--,,, / N' 0 r.õL
'-f..(!sriI
--_sjIN
;6-, 18c -):11.Boc o 18cl '-'0NH

\ / N
F
0\N-N--(cisj1N 0 0 N
Compound 18 0 Step 1:
cis-tert-butyl 4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-y1)-31-11uoro-[1,4'-bi pi peri di ne]-1'-carboxyl ate (18a) F

N
N. Boc 3-(4-phenoxyphen y1)-1-(piperi d i n-4-y1)-1H-pyrazol o [3 ,4-d] pyri mi din-4-am i ne (la) (see J. Med. Chem. 2015, 58, 9625-9638 for the synthetic method) (1.5 g, 3.8g mmol) was dissolved in 10 mL of DM50 and 50 mL of DCE, and N-Boe-3-f1uoro-4-piperidone (2.1 g, 9.70 mmol) was added, the mixture was stirred at room Date Recue/Date Received 2021-09-09 temperature for 10 minutes, and then sodium triacetoxyborohydride (4.1 g, 19.40 mmol) was added, the mixture was stirred at room temperature overnight. To the reaction solution was slowly added dropwise 80 mL of saturated sodium bicarbonate solution, and the mixed solution was extracted with 100 mL of dichloromethane.
The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/naethanol (v/v) = 20 : 1), to obtain cis tert-buty1-4-(4-amino-3-(4-phenoxypheny1)-111-pyrazolo[3 ,4-(1] pyrim idin-l-y1)-3'- fluoro-[1,4 '-b ip iperidine]- 1-(18a) (980 mg, yield: 43%).
LC-MS m/z = 588.3 [WA'.
Step 2:
cis-1-(31-fluoro-[1,4'-bipiperidin]-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-djpyrimidin-4-amine trifluoroacetate (18b) \ N
0 \ 1 =
N (cis) NH
cis-tert-butyl 4-(4-amino-3-(4-phenoxypheny1)-11-1-pyrazolo[3,4-d]pyrimidin-l-y1)-3'-fluoro-[1,4`-bipiperidine]- 1 -carboxylatc (18a) (0.5 g, 0.85 minol) was dissolved in 50 mL of DCM, and 10 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 h. The reaction system was directly concentrated under reduced pressure to obtain cis-1-(3'-fluoro-[1,4'-bipiperidin]-4-y1)-3-(4-phenoxypheny1)- I H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate (18b) (0.60 g).
LCMS m/z ---- 488.5 [M. 1]'.
Step 3:
cis-tert-butyl 3 -(4-(4-amino-3-(4 -pherioxypheny1)-1H -pyrazo lo [3,4-d]pyrimidin- I -y1)-3T-fluoro-[1,4t-bipiperidinj-l'-yl)azctidinc-1-carboxylatc (18c) Date Recue/Date Received 2021-09-09 H2N z N
(cis) cis-1-(3'-fluoro-[ I ,4t-bipiperidin]-4-y 1)-3-(4-phenoxypheny1)-1H-py razo lo [3,4-d]pyrimidin-4-amine trifluoroacetate (18b) (540 mg) was dissolved in 15 mL of 1,2-dichloroethane and 2 mL of DMSO, and tert-butyl 3-oxoazetidine-1-carboxylate (564 mg, 3.30 mmol) was added, the mixture was stirred at room temperature for 10 minutes. Sodium triacetoxyborohydride (1.4 g, 6.60 mmol) was added, and the mixture was stirred at room temperature overnight. To the reaction solution was slowly added dropwise 80 mL of saturated sodium bicarbonate solution, and the mixed solution was extracted with 50 mL of DCM. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethanc/methanol (v/v) = 20 : 1), to obtain cis-tert-butyl 3-(4-(4-amino-3 -(4 -phenoxypheny1)-1H-pyrazol o [3,4-ct] pyri mi d in-1 -y1)-3'-f1uoro-[1,4'-bi piperi din] n e-1-carboxyl ate (18c) (290 mg).
LCMS m/z = 643.3 [M+1] .
Step 4:
cis-1-(11-(azeti d in -3-y1)-3 '-fl uoro-[1,4!-bi pip erid n]-4-y])-3-(4-ph enoxyph eny1)-1H-pyrazol o[3,4-d] pyrim d in-4- am ine trifluoroacetate (18d) A

0 \ N F
(cis) cis-tert-butyl 3-(4-(4-am i no-3-(4-phenoxyphenyI)- 1 H -pyrazolo [3 ,4-d]pyrim idin-l-y1)-31-fluoro41 ,4'-bipiperidin]-1'-yl)azetidine-l-carboxyl ate (18c) (290 mg, 0.45 mmol) was dissolved in 10 rtiL of DCM, and 2 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 h. The reaction system was directly concentrated under reduced pressure to obtain cis-1-(1'-(azetidin-Date Recue/Date Received 2021-09-09 3-y1)-3'-fluoro-[1,41-bip iperidin]-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-d]pyrimidin-4-amine trifluoroacetate (18d) (0.30 g).
LCMS in/z ¨ 543.5 [M-F 1 ].
Step 5:
cis-5-(3-(4-(4-amino-3-(4-phenoxypheny0-1H-pyrazol o [3,4-d]pyri mi d n-l-y1)-3'-fluoro-[1,4'-bi piperi din] - I '-yl)azetidin-l-y1)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate (compound 18) ON \
(as) NH

cis-1-(11-(azefidin-3-y1)-31-fluoro-[1,41-bipip eridinj-4 -y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate (18d) (0.3 g) was dissolved in 8.5 mL of DMSO, and 1.5 mL of DIPEA and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (250 mg, 0.90 mmol) were added, the mixture was stirred at 80 C for 5 h. The reaction solution was cooled to room temperature, added 10 rriL of water, and extracted with 50 mL of ethyl acetate. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) ¨ 20 1), to obtain cis-5-(3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3 ,4-d] pyrimidin-l-y1)-3 '-fluoro-[1,4'-bipiperidinj-1 yl)azetidin-l-y1)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate (compound 18) (80 mg).
'H NMR (400 MHz, DMSO-d6) ii 11.05 (s, 111), 8.23 (s, 1H), 7.71 - 7.61 (in, 3H), 7.47 - 7.39 (in, 2H), 7.22 - 7.08 (m, 5H), 6.82 - 6.78 (in, 1H), 6.66 (dd, 1H), 5.11 -4.92 (m, 2H), 4.71 - 4.58 (m, 11-1), 4.15 -4.05 (m, 2H), 3.92- 3.77 (m, 2H), 3.45 -3.36 (m, 1H), 3.17 - 3.02 (m, 3H), 2.99 - 2.82 (m, 2H), 2.64 -2.53 (in, 3H), 2.47 -2.39 (n, 2H), 2.23 - 1.97 (in, 5H), 1.96- 1.79 (in, 3H), 1.75 - 1.64 (m, 1H).
Date Recue/Date Received 2021-09-09 LCMS miz = 799.3 [M+1].
Example 18-1:
cis-5-(3-(4-(4-amino-3-(4-plienoxypheny1)-1H-pyrazolo [3,4-d]pyri midin-l-y1)-3'-fiuoro-[1,4'-bi piperi di n n-l-y1)-2-(2,6-dioxopi peridin-3-yl)isoindoline-1,3-dione (compound 18-1) H2N 'N
= (cis>1 ZNji_o The compound 18(50 mg) was dissolved in 10 mL of concentrated ammonia water with a mass fraction of 28%, the mixed solution was extracted with DCM
(12 mL x 3). The organic phase was combined, and washed concentrated ammonia water with a mass fraction of 28 /0 (12 mL x 3), the organic layer was dried over anhydrous sodium sulphate, and concentrated under reduced pressure. To the residue was added 10 rriL of petroleum ether and slurried for 0.5 h, and the slurry was filtered, to obtain free base cis-5-(3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-1-y1)-3t-fluoro-[1,4'-bipiperidin]-l'-y1)azetidin-1-y1)-2-(2,6-dioxopiperidin-yfiisoindoline-1,3-dione (compound 18-1) (35 mg).
'H NMR (400 MHz, CDC13) 6 9.16 (s, 1H), 8.38 (s, 1H), 7.69 - 7.59 (m, 3H), 7.43 - 7.34 (in, 2H), 7.21 - 7.03 (in, 51-1), 6.78 (d, 1H), 6.52 (dd, 1H), 5.72 (brs, 2H), 5.20 - 4.97 (m, 1H), 4.96 -4.88 (m, 1H), 4.87 -4.73 (m, 1H), 4.16 -4.04 (m, 2H), 4.00 - 3.85 (m, 2H), 3.52 -3.43 (m, 1H), 3.36- 3.13 (m, 3H), 3.10- 3.00 (m, 1H), 2.95 -2.62 (m, 5H), 2.59 - 2.35 (m, 3H), 2.25 -2.00 (m, 6H), 1.89- 1.79 (m, 1H).
LCMS m/z .799.3 [M+1]+.
Example 19:
trans-5-(3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin- I -y1)-3-fluoropiperidin-l-y1)-[1,3t-biazetidin]-1T-y1)-2-(2,6-dioxopiperidin-3 yl)isoindoline-1,3-dione trifluoroacetate (compound 19) Date Recue/Date Received 2021-09-09 N-, H2N- \
\ / N
F
(trans) .
NH

H2N \N \,N

OH
0 \ , ' F
,..-I-L....õ-F Step I F Step 2 "", N, F
+ N. ,N

N,Boc(_____ N' Bac Bac Bac 19a 19b 19c (major) 19c (minor) H2N H2N=
\ /N F \ /N F
\NN It SwF" Step Step3 -0 x.-19c -----7\ij NH
C--' Nõ..õ.õ--\
\...-N,Bac 19d 19e N.,=-õ, H2N-= \N=z-\./ N F
H2N \ /N F Step7 St42-0) 0- -/B0- NO (,,r.
0 \N-N arans't Nõ.õ--\
N
B
19g oc 19f H2N \ / N \ õõ N
F F
Step }i _0_ (trans) 19h Compmmdlg o Step 1:
tert-butyl 3 -fluoro-4-hydroxypiperi dine- 1 - earboxy late ( 1 9b) OH
_......1,,...õ...F
6oc Date Recue/Date Received 2021-09-09 Tert-butyl 3-fluoro-4-piperidone-carboxy1ate (19a) (6.51 g, 30.0 mmol) was dissolved in 80 mL of anhydrous methanol, and sodium borohydride (2.28 g, 60.0 mmol) was slowly added in portions at room temperature. Upon completion of the addition, the mixture was stirred at room temperature for 30 minutes. The reaction solution was quenched with 150 mL of saturated sodium bicarbonate solution, and extracted with 100 niL of dichloromethane. The organic phase was washed with mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2: 1), to obtain the mixture of cis and trans isomers tert-butyl 3-fluoro-4-hydroxypiperidine- -carboxylate (19b) (5.7g. cis/trans = 2.5 : 1, yield: 87%).
LC-MS rn/z = 220.1 [M+1] .
Step 2:
trans-tert-butyl 4-(4 -amino-3-(4 -phenoxypheny1)-1H-pyrazolo [3,4 -d]pyrim idin-1 -y1)-3-fluorop iperi dine-1-carboxyl ate (19c) Fl2N \ N
F
0 'NN-N (trans) N.. Bac The mixture of cis and trans isomers tert-butyl 3-11uoro-4-hydroxypiperidine-l-carboxylate (19b) (cis/trans = 2.5 : 1) (1.0g. 4.56 mmol) and 3-(4-phenoxypheny1)-1H-pyrazolo[3,4-djpyrimidin-4-amine (1.15 g, 3.80 mmol) was dissolved in 40 mL
of THF, and triphenylphosphine (1.5 g, 5.72 mmol) was added. DIAD (1.15 g, 5.69 mmol) was slowly added dropwise under nitrogen atmosphere. Upon completion of the addition, the mixture was stirred at room temperature overnight. Upon completion of the reaction, to the system was slowly added 50 mL of saturated sodium bicarbonate solution, the mixed solution was extracted with 100 rriL of dichloromethane. The organic phase was washed with 100 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography Date Recue/Date Received 2021-09-09 (dichloromethane/methanol (v/v) = 15 : 1), to obtain trans-tert-butyl 4-(4-amino-3-(4-phenoxypheny1)-114-pyrazolo[3,4-d]pyrimidin-l-y1)-3-fluoropiperidine-1-carboxylate (19c) (0.8 g, yield: 35%).
LCMS m/z = 505.4 [M+1] .
Step 3:
tra ns-1-(3- fluorop i perid in-4-y1)-3-(4-plienoxyphe ny1)-1H-pyrazolo [3,4-d]pyrimidin-4-amine trifluoroacetate (19d) H2N iN
0 \ s'N-N arms) NH
Trans-tert-butyl 4-(4-amino-3-(4-phenoxypheny1)-111-pyrazolo [3,4-d[pyrimidin-l-y1)-3-fluoropiperidine-1-carboxylate (19c) (800 mg, 1.59 mmol) was dissolved in 20 mL of DCM, and 5 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 h. Upon completion of the reaction, the system was directly concentrated under reduced pressure, to obtain trans- I -(3-uoropi perid in -4-y1)-3-(4-ph enox yph eny1)- 11-1-pyrazol o[3,4 -d]pyri m id in -4-am in e trifluoroacetate (19d) (0.90 g).
LCMS m/z = 405.3 [M-F1]+.
Step 4:
trans -tert- butyl 3 -(4-(4-am ino-3 -(4- phenoxypheny1)-1H -pyrazolo [3,4-d]pyrim idin- 1-y1)-3 -fluoropi peridin-1 -yl)azetidine-l-carboxylate (19e) \ /N F
Ira ns-1-(3-fluoropi peridin-4-y1)-344-phenoxyphe ny1)- 1H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate (19d) (0.8 g) was dissolved in 35 mL of DCE
and 5 nit of DMSO, and tert-butyl 3-oxoazetidine-1-carboxylate (542 mg, 3.17 mmol) was added, the mixture was stirred at room temperature for 10 minutes, then sodium Date Recue/Date Received 2021-09-09 triacetoxyborohydride (1.68 g, 7.92 mmol) was added, and the mixture was stirred at room temperature overnight. To the reaction solution was slowly added 30 mL of saturated sodium bicarbonate aqueous solution, and the mixed solution was with extracted with 50 mL of ethyl acetate. The organic phase was washed with 50 mL
of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20 : 1), to obtain trans-tert-butyl 3-(4-(4- amino-3-(4-phenoxypheny1)-1H-pyrazolo[3 ,4-dipyrimidin-1 -y1)-3-fluoropiperidin-l-yl)azetidine-1 -carboxylate (19e) (930 mg).
LCMS m/z = 560.5 [M+1] .
Step 5:
trans-1-(1-(azetidin-3-y1)-3-fluoropiperidin-4-y1)-3- (4-phcnoxypheny1)-1H-pyrazo lo [3 ,4-dipyrimidin-4-amine trifluoroacetate (190 Nizz-\
F
0 N frariF.) = N
trans-tert-butyl 3-(4 -(4- amino-3-(4-pheno xypheny1)-1H-pyrazo lo [3,4-d]pyrim idin-1 -y1)-3-fluoropiperid in-1 -yl) azetidine -1-carboxyl ate (19e) (500 mg, 0.89 inmol) was dissolved in 20 mL of DCM, and 5 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 h. Upon completion of the reaction, the system was directly concentrated under reduced pressure, to obtain trans-1-(1-(azetidin-3-y1)-3-fluoropiperidin-4-y1)-3-(4-phenoxypheny1)-1I I-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate (190 (0.65 g).
LCMS m/z = 460.3 [M+ I]t Step 6:
trans-tert-butyl 3 -(4-(4-amino-3 -(4- phenoxypheny1)-1H-pyrazolo [3,4-d]pyrim id in- 1-y1)-3 - fluorop iperidin-l-y1)-[1,3t-biazetid ine] -1'-carboxylate (19g) Date Recue/Date Received 2021-09-09 Nz_--,\
F
N
-0 N(tar.) trans-1-( 1-(azeti din-3 -yI)-3 -flu oropiperid in-4-y0-3-(4-phenoxypheny1)-1H-pyrazolo[3 ,4-djpyrirnidin-4-amine trifluoroacetate (190 (650 mg) was dissolved in 25 mL of DCE and 2 mL of DMSO, and tert-butyl 3-oxoazetidine-1-carboxy1ate (485 mg, 2.83 mmol) was added, the mixture was stirred at room temperature for 10 minutes, then sodium triacetoxyborohydride (1.12g. 5.28 mmol) was added, and the mixture was stirred at room temperature overnight. To the reaction system was slowly added 60 rnL of saturated sodium bicarbonate solution, and the mixed solution was extracted with 60 mL of ethyl acetate. The organic phase was washed with 50 mL
of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20 : 1), to obtain trans-tert-butyl 3-(4-(4-amino-3-(4-phenoxyph eny1)-1 H-pyrazol o[3 ,4 -dipyri midin-1 -y1)-3-fl uoropiperidin-l-y1)-[1 ,3t-biazetidin]-11-carboxy late (19g) (450 mg).
LCMS m/z = 615.6 [MA]'.
Step 7:
trans-1-(1-([1,3'-biazetidin]-3-y1)-3-fluoropiperidin-4-y1)-3-(4-phenoxyphenyI)-1H-pyrazo lo [3 ,4-d] pyrimidin-4-amine tri fluoroacetate (19h) N
F
0 \N-N (trans) trans-tert-butyl 3 -(444-amino-3-(4-ph enoxypheny1)-1 H-pyra7o10 [3,4-d]pyrimidin-1 -y1)-3-fluorop iperi din-l-y1)-[1,3'-bi azeti din] -11-carboxylate (19g) (400 mg, 0.65 mmol) was dissolved in 20 mL of DCM, and 4 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 h. The reaction system Date Recue/Date Received 2021-09-09 was directly concentrated under reduced pressure, to obtain trans-1-(1-([1,3'-biazetidin]-3-y1)-3-fluoropiperidin-4-y1)-3-(4-phenoxypheny1)-11-1-pyrazolo [3,4-d]pyrimidin-4-ainine trifluoroacetate (19h) (0.56 g).
LCMS m/z = 515.5 [M+11 .
Step 8:
rans-5-(3-(4-(4-amino-3-(4- phenoxypheny1)- 1H-pyrazolo [3,4-d] pyrim idin-1-y1)-3-fluoropiperi din-1-y1)- [ I ,3'-biazetidin]-1T-y1)-2-(2,6-dioxopiperidin-ypisoindoline-1,3-dione trifluoroacetate (compound 19) /N
0N_NJ

1,4___Z¨NFI

trans-1-(1-([1,3'-biazetidinj-3-y1)-3- fluoropiperidin-4-y1)-3 -(4-phenoxypheny1)-1H-pyrazolo [3 ,4-d]pyrim idin-4-am in e trifi uoroacetate (19h) (0.5 g) was dissolved in 25 mL of DMSO, and 3 mL of DIPEA and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (352 mg, 1.28 mmol) were added, the reaction was stirred in an external bath at 80 C
for 5 h. The reaction solution was cooled to room temperature, added 50 mL of water, and extracted with 100 mL of ethyl acetate. The organic phase was washed with mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20 : 1), to obtain trans-5-(3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo [3 ,4-d ]pyrimid in-1 -yI)-3 -fluoropiperidin-1-y1)-[1,3'-biazetidin]-l'-y1)-2-(2,6-dioxopiperidin-3-y1)isoindoline-1,3-dione trifluoroacetate (compound 19) (120 mg).
NMR (400 MHz, DMSO-d6) 6 11.05 (s, 1H), 8.25 (s, 1H), 7.73 - 7.60 (m, 31-1), 7.48 -7.40 (m, 2H), 7.23 - 7.10 (in, 51-1), 6.80 (d, 111), 6.66 (dd, 1H), 5.25 - 5.00 (m, 2H), 4.88 - 4.75 (m, 1H), 4.12 - 4.00 (m, 2H), 3.89 - 3.78 (m, 2H), 3.75 -3.62 (m, 111), 3.54 - 3.39 (m, 21-1), 3.28 - 2.96 (m, 4H), 2.95 - 2.77 (m, 211), 2.64 -2.53 (m, Date Recue/Date Received 2021-09-09 211), 2.30 - 2.08 (m, 3H), 2.07 - 1.92 (m, 211).
LCMS m/z = 771.3 [M-4-1]+.
Example 19-1:
trans-5-(3-(4-(4-amino-3-(4-phenoxyphenyl )-1H-pyrazolo13,4-djpyrimidin-1 --y1)-3-fluoropiperidin-1-y1)41,3T-biazetidin]-1T-y1)-2-(2,6-dioxopiperidin-3-ypisoindoline-1,3-dione (compound 19-1) N, H2N , /N

c5 \N-N

The compound 19 (95 mg) was dissolved in 17 mL of concentrated ammonia water with a mass fraction of 28%, the mixed solution was extracted with DCM
(20 to mL x 3). The organic phase was combined, and washed concentrated ammonia water with a mass fraction of 28% (20 mL x 3), the organic layer was dried over anhydrous sodium sulphate, and concentrated under reduced pressure. To the residue was added 17 mL of petroleum ether and slurried for 0.5 h, and the slurry was filtered, to obtain free base trans-54344-(4-amino-3 -(4-phenoxypheny1)-1H-pyrazolo [3 ,4-is d]pyrim id in-1 -y1)-3 -fluo ropiperid in-l-y1)-[1,3'-bi azeti din]-1'-y1)-2-(2,6-dioxopiperi din-3-ypiso indol ine-1,3-dionc (compound 19-1) (80 mg).
'H NMR (400 MHz, CDC13) ö 9.30 (brs, 1H), 8.40 (s, 1H), 7.69- 7.61 (m, 3H), 7.43 - 7.35 (m, 2H), 7.21 -7.04 (m, 5H), 6.79 (d, 1H), 6.53 (dd, 1H), 5.73 (brs, 2H), 5.36 - 5.13 (m, 114), 4.97 -4.83 (m, 2H), 4.11 -4.00 (m, 214), 3.94- 3.84 (m, 21-1), 20 3.76 - 3.56 (m, 3H), 3.30 - 3.05 (m, 411), 2.93 - 2.64 (m, 411), 2.54 -2.39 (m, 111), 2.23 - 2.02 (m, 411).
LCMS rn/z = 771.3 [1\4 1]'.
Example 20:
trans-5 -(34444 -amino-3 -(4-phenoxypheny1)-111-pyrazolo [3,4-d]pyrimidin-1 25 y1)-3-fluoro-[1,4t-bipiperidin]-1'-yl)azetidin-1-y1)-2-(2,6-dioxopiperidin-3-y I) iso indo line-1, 3-dione trifluoroacetate (compound 20) Date Recue/Date Received 2021-09-09 N-, \ /N
F
-....,..õõN
d 11¨N 00 -/..N...._t NH

.. N.-_---\
\
N,A. H2N H2N \ N N
F
Step 1 Step 2 / '', -IV
0 \--- / \N-N- -al NH a- ,.., , i = , N. , Lc¨Cs, 1 N trans)1 N
ö 20a 1.,,N-130c (Ii?
20b ---19d H2N-H2N/,.._ N
F F
Step 5 Step 3 Step 4 NN-N
o \_,,,,,, b 20.1 .\¨NH
20c BOG
N--.\
H2N-1._f F
)---0 4. ''N-N'ts)IN

N
a N
z COmixxind 20 0 Step 1:
trans-tert-butyl 4-(4-am ino-3-(4-phenoxyphenyl)-11-1-pyrazo lo [3,4-d]pyr im id in-l-y1)-3-fluoro-[1,4'-hip i perid ine]-1t-earboxy late (20a) N--_--:\

\ N
i F
0 \N-N (trans) No trans-1-(3-fluoropiperid in-4-y1)-3 -(4-phenoxyphe ny1)- I H-pyrazolo [3,4-d]pyrimidin-4-amine trifluoroacetate (19d) (520 mg) was dissolved in 15 tnL of DCE
and 2 mL of DMSO, and N-Boe-4-piperidone (1.05 g, 5.27 mmol) was added, the mixture was stirred at room temperature for 10 minutes, then sodium Date Recue/Date Received 2021-09-09 triacetoxyborohydride (1.12 g, 5.28 mmol) was added, and the mixture was stirred at room temperature overnight. To the reaction system was slowly added SO mL of saturated sodium bicarbonate solution, and the mixed solution was extracted with 50 mL of DCM. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (diehloromethane/methanol (v/v) = 20 : 1), to obtain trans-tert-butyl 4-(4-amino-3-(4-phenoxypheny1)- 1 H-pyrazolo [3 ,4-d]pyrimidin- 1 -y1)-3-fluoro-[ I ,4t-bipiperidinej-F-carboxy late (20a) (500 mg).
LCMS m/z = 588.4 [M+1 r.
Step 2:
trans- I -(3-fluoro-[ 1 ,4'-bipiperi din]-4-y1)-3-(4-phenoxypheny1)- I H-pyrazolo[3,4-dipyrimidin-4-amine trifluoroacetate (20b) N.
H N
2 \ N
\ -2( F
N.N (trans) 0 =
trans-tert-butyl 4-(4-amino-3 -(4-phenoxypheny1)- 1H-pyrazolo [3,4-d]pyrimidin- 1 -y1)-3-fluoro- [1 ,4'-bipiperidine]- 1 '-earboxylate (20a) (500 mg, 0.85 minol) was dissolved in 20 mL of DCM, and 5 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 h. The reaction system was directly concentrated under reduced pressure, to obtain trans- 1-(3-fluoro-[1,41-bipiperidin]-4-y1)-3-(4-phenoxypheny1)- 1 H-pyrazolo [ 3,4-d]pyrimidin-4-amine trifluomacetate (20b) (0.60 g).
LCMS miz = 488.3 [M+ 1 ]+.
Step 3:
trans-tert-butyl 3 -(4-(4-arnino-3-(4-phenoxypheny1)- 1 H-pyrazolo [3,4-d]pyrim idin- 1-y1)-3 -fluoro-[ 1,4'-bipiperidin]-11-yl)azetidine-1-carboxylate (20c) Date Recue/Date Received 2021-09-09 N
F
0 N N (trans) =
N
Bac trans-1-(3-fluoro41,4'-bipiperidinj-4-y1)-3-(4-phenoxypheny1)- 1H-pyrazolo[3,4-djpyrimidin-4-amine trifluoroacetate (20b) (600 mg) was dissolved in 35 mL of DCE and 2 mL of DMSO, and tert-butyl 3-oxoazetidine-l-earboxylate (727 mg, 4.25 mmol) was added, the mixture was stirred at room temperature for 10 minutes, then sodium triacetoxyborohydride (900 mg, 4.25 mmol) was added, and the mixture was stirred at room temperature overnight. To the reaction system was slowly added 80 mL of saturated sodium bicarbonate solution, and the mixed solution was extracted with SO mL of DCM. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) 20 : 1), to obtain trans-tert-butyl 3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo [3 ,4-dipyrimidin-1 -y1)-3-fluoro-[1,4'-bipiperidin]-1'-yl)azetidine-1-carboxylate (20c) (550 mg).
LCMS m/z = 643.4 [M+1r.
Step 4:
trans-1-(1'-(azetidin-3-y1)-3-fluoro-[1,4'-bipiperidin]-4-y1)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-dlpyrimidin-4-amine trifluoroacetate (20d) N
H N
2 \ N
F
N N
0 N (trans) N
NH
trans-tert-butyl 34444- amino-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-d]pyrirnid in- 1-y1)-3-fluoro-[1,4'-bipiperidin]-11-yl)azetid ine-1-carboxyl ate (20c) (500 mg, 0.78 mmol) was dissolved in 25 mL of DCM, and 5 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 h. The reaction Date Recue/Date Received 2021-09-09 system was directly concentrated under reduced pressure, to obtain trans-1-(1'-(azetidin-3-y1)-3-fluoro-{1,4'-bipiperidin]-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate (20d) (0.55 g).
LCMS m/z = 543.2 [M+11 .
Step 5:
trans-5-(3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-1-y1)-3-fluoro-[1,41-bipiperidin]-1'-y1)azetidin- I -y1)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate (compound 20) 0 \ NN-N (trans)N
=

trans-1-(1'-(azetidin-3-0-3-fluoro-[1,4T-bipiperidini-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate (20d) (0.5 g) was dissolved in 25 mL of DMSO, and 3 mL of DIPEA and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (310 mg, 1.12 mmol) were added, the reaction was stirred in an external bath at 80 C
is for 5 h. The reaction solution was cooled to room temperature, added 50 mL of water, and extracted with 100 mL of ethyl acetate. Thc organic phase was washed with mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol ¨ 15 : 1-8 : 1), to obtain trans-5-(3-(4-(4-am ino-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-d]pyrimidin- 1-y1)-3-fluoro-[1,4'-bipiperidin]-1t-ypazetidin-l-y1)-2-(2,6-dioxopiperidin-3-y1)isoindol ine-1,3-dione trifluoroacetate (compound 20) (120 mg).
11-I NMR (400 MHz, DMSO-d6) 6 11.05 (s, 1H), 8.24 (s, 1H), 7.72 - 7.61 (m, 311), 7.47 - 7.40 (m, 2H), 7.22 - 7.10 (m, 511), 6.79 (d, 111), 6.65 (dd, 1H), 5.19 - 4.94 (m, 2H), 4.83 -4.70 (m, 1H), 4.15 -4.05 (m, 21-1), 3.89 - 3.76 (m, 2H), 3.41 -3.34 (m, 111), 3.00 -2.81 (m, 4H), 2.63 - 2.52 (in, 211), 2.49 - 2.32 (in, 4H), 2.24 -2.10 (in, Date Recue/Date Received 2021-09-09 111), 2.07 - 1.94 (m, 2H), L94 - 1.82 (m, 2H), 1.82 - 1.70 (m, 211), 1.57 -1.41 (m, 21-1).
LCMS in/z ¨ 799.3 [M--1r.
Example 20-1:
trans-5-(3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-1-y1)-3-fluoro-[1,41-bipiperidin]-1'-y1)azetidin-1-y1)-2-(2,6-dioxopiperidin-3-yflisoindoline-1,3-dione (compound 20-1) N., /N F
OJN _______________________________ NH

The compound 20 (90 mg) was dissolved in 17 mL of concentrated ammonia water with a mass fraction of 28%, the mixed solution was extracted with DCM
(20 mL x 3). The organic phase was combined, and washed concentrated ammonia water with a mass fraction of 28% (20 mL x 3), the organic layer was dried over anhydrous sodium sulphate, and concentrated under reduced pressure. To the residue was added 17 mL of petroleum ether and slurried for 0.5 h, and the slurry was filtered, to obtain free base trans-5-(3-(4-(4-amino-3 -(4-phenoxypheny1)-1H-pyrazolo [3 ,4-d]pyrimidin-l-y1)-3-fluoro-[1,4'-bipiperidin]-1`-y1)azetidin-1-0-2-(2,6-dioxopiperi din-3-ypiso indoline-1,3-dione (compound 20-1) (70 mg).
111 NMR (400 MHz, CDC13) 6 8.86 (brs, 1H), 8.39 (s, 111), 7.71 - 7.60 (in, 3H), 7.43 - 7.35 (m, 2H), 7.21 -7.11 (m, 3H), 7.11 - 7.04 (m, 2H), 6.79 (d, 1H), 6.53 (dd, 11-1), 5.78 (brs, 2H), 5.33 - 5.10 (m, 1H), 4.97 -4.81 (m, 211), 4.16 - 4.06 (m, 2H), 4.00 - 3.86 (in, 2H), 3.48 - 3.34 (m, 2H), 3.08 - 2.94 (m, 3H), 2.93 - 2.65 (m, 311), 2.59 - 2.36 (m, 411), 2.17- 1.97 (m, 411), 1.96- 1.85 (m, 211), 1.78 - 1.62 (m, 2H).
LCMS m/z = 799.3 [M+1]1.
Example 21:
5-(3 -(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-d]pyrimidi n-1-yl)piperi din-l-y1)-[1,3'-bi azeti din] -1'-y1)-2-(2,6-dioxopi peridi n-3-y1)-Date Recue/Date Received 2021-09-09 fluoroisoindo1ine-1,3-dione (compound 21) N ,N

OH OH Step FNo Step 2 21a 21b Q orµs_Ny0 N-Cumptitmti 21 0 Step 1:
2-(2,6-dioxopiperidin-3-y1)-5,6-difluoroisoindo1ine-1,3-dione (21b) NH

4,5-difluorophthalic acid (21a) (500 mg, 2.47 mmol) was dissolved in 25 mL of acetonitri le, and 3-aminopiperidine-2,6-dione hydrochloride (0.41 g, 2.49 mmol) and CDI (0.8 g, 4.94 mmol) were added, the mixture was heated to reflux in external bath, and reacted for 4 h. The reaction system was directly concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2 : 1), to obtain 242,6-dioxopiperidin-3-y1)-5,6-difluoroisoindoline-1,3-dione (21b) (0.4 g, yield:
55.0%).
LCMS tn/z ¨ 295.2 [M+1]'.
Is Step 2:
5-(3-(4-(4-amino-3-(4-phenoxypheny1)-11-1-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-l-y1)-[1,3t-biazetidini-l'-y1)-2-(2,6-dioxopiperidin-3-y1)-6-Date Recue/Date Received 2021-09-09 fluoroisoindoline-1,3-dione (compound 21) H2 \

-N

1 -[1 -[1- (azeti -yl)azeti din-3 -y1]- 4-piperi clyl] -3-(4-phenoxyphenyl)pyrazolo[3,4-d]pytimidin-4-amine (17d) (0.25 g, 0.50 mmol) was dissolved in 10 mL of DMSO, and 1 mL of D1PEA and 2-(2,6-dioxopiperidin-3-y1)-5,6-difluoroisoindoline-1,3-dione (21b) (180 mg, 0.61 mmol) were added, the mixture was stirred in external bath at 80 C for 5 h. The reaction solution was cooled to room temperature, quenched by adding 50 mL of water, and extracted with 100 mL of ethyl acetate. The organic phase was washed with 100 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/inethanol (v/v) = 15 : 1), to obtain 5-(3-(4-(4-amino-3-(4-phenoxyphenyI)-1H-pyrazo lo [3 ,4-d]pyrimidin-1 -y Opiperidi n-1 -y1)-[1,3 '-bi azeti din] -F-y1)-2-(2 ,6-dioxopi peri din-3-y1)-6-fluoroi soindoline-1,3 -di one (compound 21) is (100 mg, yield: 26%).
'H NMR (400 MHz, DMSO-d6) 6 11.07 (s, 1H), 8.23 (s, 1H), 7.70 - 7.63 (m, 2H), 7.58 (d, 1H), 7.48 - 7.40 (m, 2H), 7.22 - 7.09 (m, 5H), 6.92 (d, 1H), 5.06 (dd, 111), 4.74 - 4.61 (m, 111), 4.24 - 4.14 (m, 211), 4.00- 3.88 (m, 211), 3.66 -3.55 (m, 1H), 3.49 - 3.39 (m, 2H), 3.08 - 2.78 (m, 6H), 2.64- 2.52 (m, 2H), 2.29 - 2.13 (m, 21-1), 2.09 - L96 (m, 3H)71.96 - 1.85 (m, 214).
LCMS m/z = 771.3 [M 1].
Example 22:
443444444-amino-3-(4-phenoxyphenyppyrazolo[3,4-d]pyrimid in- 1-y1]-1 piperidy1]-1-piperidyl]azetidin-l-y1]-2-(2,6-dioxo-3-piperidyl)i so indo linc-1,3-dione (compound 22) Date Recue/Date Received 2021-09-09 0 _r NH

N¨ 0 Step I 0 H2N \ N H2N)-8b Compound 22 1 ¨( V-(azetidin-3-y1)41,4'-bipiperidin1-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo{3,4-d}pyrimidin-4-amine (8b) (0.12 g, 0.23 mmol) was dissolved in 3 mL
of DMSO, and 0.2 mL of DIPEA and 2-(2,6-dioxopiperidin-3-y1)-4-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (90 mg, 0.30 mmol) were added, the mixture was stirred in external bath at 90 C for 5 h. The reaction solution was cooled to room temperature, and extracted with 50 mL of ethyl acetate. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20 : 1), to obtain 4434444-114-amino-3-(4-phenoxyphenyl)pyrazolo [3,4-d]pyrimid in-l-yl] -1-p iperidyl] -1-piperidyl]azetid in-1-yli-2-(2,6-dioxo-3-piperidypisoindol ine-1,3-dione (compound 22) (58 mg, yield:
32%) 'H NMR (400 MHz, CDC13) 6 8.41 (s, 1H), 8.34 (s, 1H), 7.63 (d, 2H), 7.48 -7.35 (m, 31-1), 7.22 - 7.11 (m, 4H), 7.10 - 7.05 (m, 2H), 6.60 (d, 1H), 5.80 (brs, 21-1), 4.92 (dd, 1H), 4.87 - 4.68 (m, 1H), 4.44 - 4.31 (m, 2H), 4.11 -4.01 (m, 2H), 3.30 -3.08 (m, 3H), 3.02 - 2.93 (m, 2H), 2.92 - 2.68 (m, 4H), 2.63 - 2.39 (n, 4H), 2.14 -2.09 (n, 3H), 1.99 - 1.89 (n, 4H), 1.77 - 1.62 (rt, 2H).
LCMS m/z = 781.3 [M+1]'.
Example 23:
54443- [444-amino-3-(4-phenoxyphenyl)pyrazolo [3,4-d]pyrimid in-l-y1]-1-piperidyl]azetidin-l-y1]-1-piperidy1]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione Date Recue/Date Received 2021-09-09 (compound 23) =

ONO
¨N

Q _1.4_0 Boo =

N.
Step 2 N ,kiN r N
H2N \ N
lib 23a =_CNN

0 / Step N
td /N
23b Compound 23 Step 1:
tert-butyl 443[4[4-amino-3-(4-phenoxypheny 1)pyrazolo[3,4-d]pyrimid yl] -1-piperidyl] azetid in- 1-yljpiperidine-l-carboxylate (23a) N=
1-[1-(azetidin-3-y1)-4-p iperidyl] -(4-phenoxyphenyl)pyrazolo [3,4-djpyrimidin-4-amine (11 b) (0.12 g, 0.27 mmol) was dissolved in 5 nit of DCE, and tert-butyl 4-oxopiperidine-1 -carboxylate (0.5 g, 3.0 mmol) was added. The mixture was stirred at room temperature for 10 minutes, then sodium triacetoxyborohydride (0.6 g, 3.0 mmol) was added, and the mixture was stirred at room temperature overnight. To the reaction solution was slowly added dropwise 30 mL of saturated sodium bicarbonate solution, and the mixed solution was extracted with 30 ML
of dichloromethane. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude Date Recue/Date Received 2021-09-09 product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20 : 1), to obtain tert-butyl 4434444-amino-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-l-y11- 1-piperidy flazetidin- 1-y lipiperidine-1-carboxylate (23a) (0.15 g, yield: 88%).
LC-MS m/z = 625.3 [M+1]'.
Step 2:
3 -(4-phenoxyphenyl)-1- [1 -[1-(4 -piperidypazetidin-3 -y1]-4-piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (23b) # NH
N=
Tert-butyl 4 -[3 -[4- [4-amino-3 -(4-phenoxyph enyl)pyrazola [3 ,4-d]pyrimid in-1 -yl] -1-piperidyl] azetid in-1 -yl] piperidine-l-carboxylate (23a) (0.15 g, 0.24 mmol) was dissolved in 5 mL of DCM, and 1.5 mL of trifluoroaeetic acid was added, the mixture was stirred at room temperature for 3 h. To the reaction solution was slowly added dropwise saturated sodium bicarbonate solution to adjust the p1-1 to 9-10, and the mixed solution was extracted with 30 mL of dichloromethane. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain 344-phenoxypheny1)-1-[1-[1-(4-piperidypazetidin-3-y1]-4-piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (23b) (0.12 g, yield: 95%).
LCMS m/z = 525.3 [M+1]1.
Step 3:
54443- [444-amino-3-(4-phenoxyphenyl)pyrazolo [3 ,4-d]pyrimid in-l-y1]-1-piperidy liazetiditi-l-y1]-1-piperidyl]-2-(2,6-dioxo-3-piperidyl)isoindol ine-1,3-dione (compound 23) Date Recue/Date Received 2021-09-09 3 -(4-phenox ypheny1)-1-[1 -[1-(4-piperidyl )azetidin-3-y1]-4-piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (23b) (0.12 g, 0.23 mrnol) was dissolved in 3 mL of DMSO, and 0.4 mL of DIPEA and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (90 mg, 0.30 mmol) were added, the mixture was stirred in external bath at 90 C for 5 h. The reaction solution was cooled to room temperature, and extracted with 50 iriL
of ethyl acetate. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica 2e1 column chromatography (dichloromethane/methanol (v/v) = 20 : 1), to obtain 5-14-13-1444-amino-3-(4-phenoxyphenyl)pyrazolo [3,4-d]pyri mi din-l-y11-1-piperi dyflazeti di n-1-y11-piperidy11-2-(2,6-dioxo-3-piperidypisoindoline-1,3-dione (compound 23) (6 mg, yield: 4%).
is 11-1 NMR (400 MHz, CDC13) 6 8.55 (s, 111), 8.33 (s, 1H), 7.67 (d, 114), 7.64 -7.58 (m, 2H), 7.41 - 7.34 (m, 2H), 7.27 - 7.24 (m, 1H), 7.19 - 7.10 (in, 3H), 7.09 -7.01 (m, 3H), 5.80 (brs, 2H), 4.92 (dd, 1H), 4.86 - 4.75 (m, [H), 4.22 -4.04 (rn, 211), 3.98 - 188 (m, 2H), 3.54 - 3.34 (m, 3H), 103 - 2.68 (m, 8H), 2.49 - 2.33 (in, 3H), 2.28 - 2.06 (m, 5H), 2.00- 1.93 (m, 314).
LCMS m/z = 781.3 [M+1]'.
Example 24:
5-[3-[3- [4-[4-amino-3-(4-phenoxyphenyl)pyrazol o [3 ,4-d]pyri mid in- 1-y11-1-piperidyl]pyrrolidin- 1-yl]azetidin-1-y11-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (compound 24) Date Recue/Date Received 2021-09-09 110 N, N

N

N--=/
Cc,3 0 N,N
-_01 NH
/ N
\ N

16d Compound 24 1 4 1 41-(azetidin-3-yppyrrolidin-3-y1]-4-piperidyl]-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine (16d) (0.1 g, 0.20 mmol) was dissolved in 3 nriL of DMSO, and 0.2 mL of D1PEA and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (75 mg, 0.27 mmol) were added, the mixture was stirred in external bath at 90 C for 5 h. The reaction solution was cooled to room temperature, extracted with 50 mL of ethyl acetate. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20 : 1), to obtain 5-[3-[3-[4-[4-amino-3-(4-phenoxyphenyl)pyrazolo azctidin-l-y1]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dionc (compound 24) (30 mg, yield: 20%).
1H NMR (400 MHz, CDC13) S8.75 (s, 111), 8.36 (s, 111), 7.67 - 7.62 (in, 3H), 7.43- 7.36(m, 2H), 7,21 -7.12 (m, 3H), 7.11 -7.07 (m, 2H), 6.79 (d, 1H), 6.52 (dd, 1H), 5.74 (brs, 2H), 4.93 (dd, 1H), 4.88 -4.76 (m, IH), 4.14 - 4.06 (m, 2H), 3.97 -3.89 (m, 2H), 3.62 - 3.53 (m, 1H), 3.28 - 3.16 (m, 1H), 3.15 -3.00 (m, 2H), 2.97 -2.70 (m, 6H), 2.67 - 2.58 (rn, 111), 2.57 - 2.39 (in, 4H), 2.35 - 2.23 (m, 2H), 2.16 -2.09 (m, 3H).
LCMS m/z = 767.3 [M+
Example 25:
34543- [44444-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-l-y11- 1.-piperidy1]-1-piperidyflazetidin-l-ylj-1-oxo-isoindolin-2-yl]piperidine-2,6-dione Date Recue/Date Received 2021-09-09 (compound 25) = 0 0 If/LH
NY O

N, N
/ \ H2N N
p 0 ?¨"NH

SIcep 1 H2N \N H2N \ N
N=-/
8b Compound 25 1-(1'-(azetidin-3 -y1)-[1,4 -bipiperidin]-4-y1)-3-(4-phenoxyphenyI)-1H-pyrazolo[3,4-d}pyrimidin-4-amine (8b) (0.635 g, 1.21 mmol) was dissolved in 12 mL
of 1,4-dioxane, and 3-(5-bromo- 1-oxo-isoindolin-2-yl) piperidine-2,6-dione (see J.
Med. Chem. 2018, 6/, 492-503 for the synthetic method) (0.587 g, 1.82 mmol) and cesium carbonate (1.17 g, 3.63 mmol) were successively added. Nitrogen replacement was carried out three times, and methanesulfonic acid(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1t-biphenyl)(2-amino-1,11-biphenyl-yl)palladium (11) (RuPhos-Pd-G3) (0.300 g, 0.363 mmol) was added. Upon completion of the addition, nitrogen replacement was carried out three times, and the reaction was stirred in a sealed tube at 100 C for 2 h. The reaction solution was cooled to room temperature, and added 20 mL of diehloromethane and 10 mL of water.
The liquid separation was conducted, the aqueous layer was further extracted with 20 mL
of dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) ---- 100 : 0-19 : 1), to obtain 345-[34444-[4-amino-3-(4-phertoxypheny1)pyrazoloP,4-dipyrimidin-l-y11-1-piperidy1}- I -piperidyljazetidin- 1 -y1]-1 -oxo-isoindolin-2-yl]piperidine-2,6-dione (compound 25) (0.045 g, yield 5%).
111 NMR (400 MHz, DMSO-d6) 6 10.92 (s, 1H), 8.24 (s, 1H), 7.69 - 7.63 (m, 2H), 7.49 (d, 1H), 7.47 -7.40 (in, 2H), 7.22 - 7.08 (in, 5H), 6.54 -6.46 (in, 2H), 5.03 Date Recue/Date Received 2021-09-09 (dd, 114), 4.80 - 4.62 (m, 11-1), 4.25 (dd, 214), 4.05 - 3.95 (m, 2H), 3.74-3.63 (m, 211), 3.36 - 3.28 (m, 114), 3.20 - 2.97 (m, 2H), 2.96 - 2.83 (m, 314), 2.64 - 2.09 (m, 71-1), 2.05 - 1.74 (in, 7H), 1.65- 1.43 (in, 2H).
LCMS m/z = 767.4 [M+1,1 .
Example 26:
34543-[314- [4-a mino-3-(4-phenoxyphenyl)pyrazol o[3,4 -d]pyri mid i n-1-y1]-piperidyl]azetidin-l-yl]
(compound 26) o o N
= \ N H2N

_CNN
tiler)] N, _CN
N
H2N N N2N \Ist 1 7d compound 26 1 -[1-[1-(azetidin-3 -yl)azetidin-3 -y1]-4-piperidy11-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine (17d) (0.600 g, 1.21 mmol) was dissolved in 12 mL of 1,4-dioxane, and 3-(5-bromo- 1 -oxo-isoindolin-2-y1) piperidine-2,6-di one (see J. Med. Chem. 2018, 61, 492-503 for the synthetic method) (0.586 g, 1.81 mmol) and cesium carbonate (1.17 g, 3.63 mmol) were successively added. Nitrogen replacement was carried out three times, and methanesulfonic acid(2-dicyclohexylphosphino-2t,6'-diisopropoxy-1,1t-biphenyl)(2-amino-1,1r-biphenyl-2-y1)palladium (II) (RuPhos-Pd-G3) (0.300 g, 0.363 mum') was added.
Upon completion of the addition, nitrogen replacement was carried out three times, and the mixture was stirred in a sealed tube at 100 C for 2 h. The reaction solution was cooled to room temperature, and added 20 mL of dichloromethane and 10 triL
of water. The liquid separation was conducted, the aqueous layer was further extracted with 20 mL of dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography Date Recue/Date Received 2021-09-09 (dichloromethane/methanol (v/v) = 100 : 0-19: 1), to obtain 3-[5-[3-[3-[4-[4-amino-3-(4-pherioxyphenyl)pyrazolo[3,4-d]pyrimidin-l-y11-1-piperidyllazetidin-1-y1lazetidin-1-y11-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (compound 26) (0.053 g, yield: 6%).
'H NMR (400 MHz, DMSO-d6) 6 10.91 (s, 1I1), 8.23 (s, 1H), 7.70- 7.63 (m, 2H), 7.52 - 7.40 (m, 3H), 7.23 - 7.08 (in, 5H), 6.55 - 6.44 (in, 2H), 5.03 (dd, 1H), 4.72 - 4.61 (m, 1H), 4.24 (dd, 2H), 3.99 - 3.87 (m, 2H), 3.74 - 3.58 (m, 3H), 3.48 -3.36 (m, 21-1), 3.04 - 2.78 (m, 6H), 2.64 - 2.52 (m, 111), 2.41 - 2.28 (m, 1H), 2.25 - 2.14 (m, 211), 2.07 - 1.83 (m, 511).
LCMS m/z = 739.3 [M+1] .
Example 27:
44343- [444-amino-3-(4-phenoxyphenyl)pyrazolo [3,4-d]pyrimid in- 1-y1]-1-piperidyllazetidin-l-y flazetidin-l-y11-2-(2,6-dioxo-3-p iperidyl)isoindoline-1,3-dione (compound 27) 111` c-N-o -0 CN
N-H2N \ N NH
N=2"

f"NH Q p7u I

Step 0 N

I-NN H2N / \N
Q:,1H
N¨/lid Compound 27 0 1 4 1-[1-(azetidin-3-yl)azetidin-3-y1]-4-piperidy11-3-(4-phenoxyphenyppyrazolo[3,4-d]pyrimidin-4-amine (17d) (0.100 g, 0.201 mmol) was dissolved in 2 nth of dimethyl sulphoxide, and 2-(2,6-dioxopiperidin-3-y1)-4-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (0.0667 g, 0.242 mmol) and diisopropylethylamine (0.130 g, 1.01 mmol) were successively added. Upon completion of the addition, the reaction was carried out at 90 C
for 2 h.
The reaction solution was cooled to room temperature, to which 10 mL of water was slowly added dropwise, and filtered. The filter cake was dissolved with 20 mL
of Date Recue/Date Received 2021-09-09 dichloromethane, then washed with 5 mL of saturated sodium chloride solution.
The liquid separation was conducted, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) =
100 : 0-19 : 1), to obtain 443434414-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-l-y11-1-piperidyl]azetidin-l-qazetidin-l-y11-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (compound 27) (0.063 g, yield: 42%).
'1-1 NMR (400 MHz, DMSO-d6) 6 11.05 (s, 1H), 8.23 (s, 1H), 7.69 - 7.63 (m, 211), 7.56 (dd, 111), 7.47 - 7.40 (m, 211), 7.23 - 7.08 (m, 611), 6.79 (d, 111), 5.05 (dd, 1H), 4.72 - 4.62 (m, 1H), 4.25 - 4.14 (m, 211), 4.00- 3.90 (m, 2H), 3.57 -3.48 (m, 11-1), 3.47 - 3.39 (m, 2H), 104 - 2.78 (in, 6H), 2.63 - 2.45 (m, 2H), 2.27 -2.13 (m, 21-1), 2.07 - 1.83 (in, 5H).
LCMS m/z = 753.3 [M-F-1]+.
Example 28:
5-[343-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-y1]-1-piperidyflazetidin-1-yllazetidin- 1 -y1]-2-(2,6-dioxo-3-piperidyl )isoindoline-1,3-dione (compound 28) .2N

¨N
Date Recue/Date Received 2021-09-09 er) 0cc F"' õ slep 1 SteP 2 SECP3 "
N=
rN
-Ht, zN
'14 tkti--4.
N=i N=1 N
260 7ELt Pn` Ei .N
SLOp 4 Sari)r.
:5 -7" N

P4=-.
280 28c _403 0 1-1)-4.2,-NH
-Hi4 N"
1;1 CUiripOkUld Step 1:
tert-butyl 3-[(3R)-344-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-dlpyrimidin-1-y1]-1-p iperi dyl ]azetidi n e-1-carboxyl ate (2811) Bac \ N H2N
N=7 (R)-3 -(4-pheno xyphe ny1)- 1-(pi perid in-3 -y1)- 1H- pyrazo lo [3 ,4-d]
pyrimi din-4-amine (28a) (1.00 g, 2.59 mmol) was dissolved in 10 mL of chloroform, and tert-butyl 3-oxoazetidine- -carboxylate (0.665 g, 3.88 mmol) and glacial acetic acid (0.311 g, 5.18 mmol) were successively added. Upon completion of the addition, the reaction was carried out at 70 C for 3 h, and cooled to room temperature, then sodium triacetoxyborohydride (1.10 g, 5.18 mmol) was added. Upon completion of the addition, the reaction was carried out at room temperature for 2 h. Upon completion Date Recue/Date Received 2021-09-09 of the reaction, the pH was adjusted to 9-10 by adding dropwise saturated sodium bicarbonate solution. The reaction solution was concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 100 : 0-19 : 1), to obtain tell-s butyl 3-[(3R)-3- [4-am ino-3-(4-phenoxyphenyl)pyrazolo [3 ,4-d]pyrim 1din-l-y11-1-piperidyflazetidine-1-carboxylate (28b) (0.600 g, yield; 43%).
LCMS m/z = 542.2 [M+1]+.
Step 2:
1 -[(3R)-1-(azetidin-3 -y1)-3-piperi dy1]-3 -(4-phenoxyphenyl)pyrazolo [3,4-(I] pyri m idin-4-am ine (28c) =
N, N
\ H2N N
N=/
Tert-butyl 3 -[(3R)-3- [4-amino-34 4-phenoxyphenyl)pyrazolo [3 ,4-eljpyrim idin-1-y1]-1-piperidyljazetidine-1-earboxylate (28b) (0.600 g, 1.11 mrnol) was dissolved in 2 mL of dichlorornethane, and 10 mL of 4 N ethyl acetate hydrochloride solution was added, the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, then to the residue was added 20 mL
of dichloromethane, and the pH was adjusted to 9-10 with saturated sodium bicarbonate solution. The liquid separation was conducted, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain 1-[(31()-1-(azetidin-3-y1)-3-piperidy1]-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine (28e) (0.450 g, yield: 92%).
LCMS m/z = 442.2 [M+1]-1-.
Step 3:
tert-butyl 3-[3 -R3R)-314-amino-3-(4-phenoxyphertyppyrazolo [3,4-d]pyrimidin-l-y11-1-piperidyljazetidin-l-yllazetidine-1-carboxylate (28d) Date Recue/Date Received 2021-09-09 Boc ( \N
=\N
\ N

1-[(3R)-1-(azetidin-3 -y1)-3 -p iperidy1]-3 -(4-phenoxyphenyl)pyrazolo [3,4-d]pyrimidin-4-amine (28c) (0.300 g, 0.680 mmol) was dissolved in 10 m1_, of chloroform, tert-butyl 3-oxoazetidine-l-carboxylate (0.174 g, 1.02 mmol) and glacial acetic acid (0.0816 g, 1.36 mmol) were added. Upon completion of the addition, the reaction was carried at 70 C for 3 h, and cooled to room temperature, then sodium triacetoxyborohydride (0.288 g, 1.36 mmol) was added. Upon completion of the addition, the reaction was carried out at room temperature for 2 h. Upon completion of the reaction, the pH was adjusted to 9-10 by adding dropwise saturated sodium to bicarbonate solution. The reaction solution was concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 100 : 0-19 : 1), to obtain tert-butyl 3-[3-[(3R)-3- [4-amino-3-(4-phenoxypheny1)pyrazolo[3,4-d]pyrimidin-l-y1]

piperidyliazetidin-1-yliazetidine-l-carboxylatc (28d) (0.090 g, yield: 22%).
LCMS miz = 597.3 [M+1]'.
Step 4:
1 -[(3R)-1- [1-(azetidin-3 -yl)azetidin-3-yl] -3-piperidyI]-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine (28e) 1111 <, N, N
\ H2N N
N=/.
Date Recue/Date Received 2021-09-09 Tert-butyl 3 -[3- [(3 R)-344- amino-3 -(4-phenoxypheny ppyrazo lo [3,4-d]pyrimidin-1 -yI]-1 -piperidyl] azetidin-1 -yl] azetidine-l-c arboxylate (28d) (0.090 g, 0.15 mmol) was dissolved in 2 mL of dichloromethane, and 5 itiL of 4 N ethyl acetate hydrochloride solution was added, the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, then to the residue was added 20 mL of dichloromethane, and the pH was adjusted to 9-10 with saturated sodium bicarbonate solution. The liquid separation was conducted, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain 1-[(3 R)- 1-El -(azetidi n-3-ypazetidin-3-y1]-3-piperidy1}-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine (28e) (0.075 g).
LCMS m/z = 497.3 [M+1]' Step 5:
54343- [(3R)-3-1-4-amino-3 -(4-phenoxyphenyl)pyrazolo [3 ,4-d]pyrimidin-1 -yll-1-p iperidyliazetidin- 1 -yl]azetidin- 1 -y1]-2-(2,6-d ioxo-3-piperidyl)isoindoline-1, 3-dione (compound 28) =

NH

N, N
1-[(3 R)-1- [1 -(azctidin-3 -y1) azetidin-3-y1]-3 -piperidyl 1-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine (28e) (0.075 g, 0.201 mmol) was dissolved in 2 mL of dimethyl sulphoxide, and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (0.050 g, 0.066 mmol) and diisopropylethylamine (0.098 g, 0.76 mmol) were added. Upon completion of the addition, the reaction was carried out at 90 C for 2 h. The reaction solution was cooled to room temperature, to which 10 mL of water was slowly added dropwise, and filtered. The filter cake was dissolved with 20 mL of dichloromethane, then washed with 5 mL of saturated sodium chloride solution. The liquid separation Date Recue/Date Received 2021-09-09 was conducted, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) ¨ 100 : 0-9 : 1), to obtain 543 434(3 R)-3 [4-amino-3 -(4-phenoxyph enyl)pyrazolo [3 ,4-d jpyrimidin- I -yl j- 1 -piperidyl]azetidin- 1 -yljazetidin- 1 -y11-2-(2,6-dioxo-3-piperidyl)isoindoline- 1 ,3-dion e (compound 28) (0.050 g, yield: 44%).
111 NMR (400 MHz, DMSO-do) ö 11.04 (s, 1H), 8.24 (s, 1H), 7.68 - 7.59 (m, 31-1), 7.47 - 7.39 (m, 2H), 7.22 - 7.09 (m, 5H), 6.77 (d, 11-1), 6.64 (dd, 1H), 5.04 (dd, 111), 4.83 - 4.72 (m, 111), 4.06 - 3.98 (in, 211), 3.82 - 3.73 (m, 211), 3.66 -3.56 (m, 111), 3.45 - 3.32 (m, 2H), 3.06 - 2.72 (in, 6H), 2.63 - 2.45 (in, 2H), 2.37 -2.27 (m, 11-I), 2.07 - 1.95 (in, 3H), 1.90 - 1.78 (m, 2H), 1.72 - 1.58 (m, 1H).
LCMS m/z = 753.4 [M+1].
Example 29:
5-(3-(3-(4-amino-3-(4-phenoxypheny1)- 1 H-pyrazolo [3,4-ci] pyri mi di n- 1 -yl)pyrrolidin- 1 -y1)-[ 1 ,3'-biazetidi n]- -y1)-2-(2,6-dioxopiperidin-3-yl)isoindo1ine-1,3-dione trifluoroacetate (compound 29) N N N--CN / \

Date Recue/Date Received 2021-09-09 N,-,,,, H2N 1,4N H2N¨ \ `N
rcr__.0 Step I
0H k: ,tep , _ 0_0ms s,,r, 3 Step 4 ---- f )\1N--0 Y 0 \ /
N'N
µ.
13oc". Boc' Boc).4 ¨' = N 'OM
µ1300 Ci 299 29b 29c 29d 29e No H2N--1 i N
( H2N \ i N H2N \N'''' \N
Step 5 ______,, = sN , NTh7 Step 6 ---------------------------------------------- 0 N NL.r.õ...\ Si op 7 0 / ' ____ *- 0 '`--N
L.I4 N
so 29f b-f7,1, o 29g b C5 NH 29b Bum ' N----,,, --..-N
i i2Ny N I
Snp 7 i 01 'N'N---a Swp 8 H2N

b N / \
H
29i Compound 29 I =0 t"--11\IH
Step 1:
tert-butyl 3-hydroxypyrrolidine-1-carboxylate (29b) ,N1D--0F1 Bac s Tert-butyl 3-oxo pyrrolidine- 1 -carboxylate (29a) (5.56 g, 30.0 mmol) was dissolved in 80 aiL of anhydrous methanol, and sodium borohydride (2.28 g, 60.0 mmol) was slowly added in portions. Upon completion of the addition, the mixture was stirred at room temperature for 30 minutes. Upon completion of the reaction, the reaction was quenched by adding 150 mL of saturated sodium bicarbonate solution, to and extracted with 200 mL of DCM. The organic phase was washed with 100 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2 : 1), to obtain tert-butyl 3-hydroxypyrrolidine-1-carboxylate (29b) (4.7 g, yield: 84%).
is LC-MS m/z ¨ 188.1 [M Ir.
Step 2:
tert-butyl 3-((methylsulfonyl)oxy)pyrrolidine-l-carboxylate (29c) 0---oms Boc' Date Recue/Date Received 2021-09-09 Tert-butyl 3-hydroxypyrro1idine- 1 -carboxylate (29b) (1.0 g, 5.34 mmol) was dissolved in 30 mL of dichloromethane, and DIPEA (2.1 g, 16.25 mmol) was added, then MsC1 (0.74 g, 6.41 mmol) was slowly added dropwise at room temperature.
Upon completion of the addition, the mixture was stirred at room temperature for 2 h. To the reaction solution was added 40 mL of water, and the resulted solution was extracted with 100 inL of DCM. The organic phase was washed with 100 nil. of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 5 : 1), to obtain tert-butyl 3-1 -carboxylate (29c) (1.4g. yield: 98%).
LC-MS m/z = 266.2 [WA'.
Step 3:
tert-butyl 3-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-l-y1) pyrroli ditie-l-carboxyl ate (29d) hi2N
rJ
Bloc Tert-butyl 3-((methylsulfonyl)oxy)pyrrolidine- 1 -carboxylate (29c) (1.0 g, 3.77 mmol) and 3-(4-phenoxypheny1)-1H-pyrazolo[3,4-dipyrimidin-4-amine (0.75 g, 2.48 mmol) was dissolved in 40 mL of DMF, and potassium carbonate (1.24 g, 8.99 mmol) was added, the reaction was stirred at 80 C for 4 h. The reaction solution was zo cooled to room temperature, added 50 mL of water, and extracted with 100 triL of ethyl acetate. The organic phase was washed with 100 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 15 : 1), to obtain tert-butyl 3-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3 ,4-d]pyrimidin-1-yl)pyiToli dine-1 -carboxylate (29d) (0.91 g, yield: 78%).
LCMS m/z = 473.4 [M+ 1 ].
Date Recue/Date Received 2021-09-09 Step 4:
3-(4-phenoxypheny1)-1-(pyrrolidin-3-y1)-1H -pyrazo to [3 ,4-d]pyrimidin-4-amine trifluoroacetate (29e) Fi2N
\ IN
\ N

Tert-butyl 3 -(4-amino-3 -(4-phenoxypheny1)-1H -pyrazolo [3 ,4-d]pyrimid in-1-yl)pyrrolidine- I -earboxylate (29d) (910 mg, 1.87 mmol) was dissolved in 20 mL of DCM, and 8 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 h. The reaction system was directly concentrated under reduced pressure, to obtain 3-(4-phenoxypheny1)-1-(pyrrolidin-3-y1)- 1H-pyrazo lo[3,4-d]pyrimidin-4-amine trifluoroacetate (29e) (1.1 g).
LCMS m/z ¨ 373.3 [M 1]t Step 5:
tert-butyl 3 -(3-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-d]pyri mid in-1 -yl)pyn-olidin-l-yl)azetidine-1 -carboxylate (290 N=.=\

Is Ns Boc 3-(4-phenoxypheny1)-1-(pyrrolidin-3-y1)-1H -pyrazo lo [3 ,4-d]pyrimidin-4-amine trifluoroacetate (29e) (420 mg) was dissolved in 15 mL of DCE and 2 inL
of DMSO, and Boe-azetidinone (253 mg, 1.48 mmol) was added, the mixture was stirred at room temperature for 10 minutes, then sodium triacetoxyborohydride (628 mg, 2.96 rnmol) was added, and the mixture was stirred at room temperature overnight.
To the reaction system was slowly added 30 mL of saturated sodium bicarbonate solution, and the resulted solution was extracted with 100 mL of DCM. The organic phase was washed with 100 mL of water, dried over anhydrous sodium sulphate, and Date Recue/Date Received 2021-09-09 concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) =
20:
1), to obtain tett-butyl 3 -(3-(4-amino-3 -(4-phenoxyphenyI)-1H-pyrazo10 [3,4-d jpyrimidin- I -y1 )pyrro lid in-l-yl)azetidi ne-1 -carboxylate (29t) (320 mg).
LCMS in/z = 528.5 [M-F-1]-1".
Step 6:
1-(1-(azetidin-3-yl)pyrrol idin-3-y1)-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-d]pyrimidin-4-amine trifluoroacetate (29g) =

NH
Tert-butyl 3-( 3-(4-amino-34 4-phenoxypheny1)-1H-pyrazolo [3,4 -djpyrimidin-1 -yl)pyrrol id in- 1 -ypazetidine-l-carboxyl ate (291) (320 mg, 0.61 mmol) was dissolved in 20 mL of DCM, and 5 inL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 h. The reaction system was directly concentrated under reduced pressure, to obtain 1-(1-(azetidin-3-yl)pyrrolidin-3-y1)-3-(4-phenoxypheny1)-111-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate (29g) (380 mg).
LCMS m/z = 428.4 [M+1]+.
Step 7:
tert-butyl 3 -(3-(4-amino-3 -(4-phenoxypheny1)-1H-pyrazolo [3 ,4-d]pyrimidin-1 yl)pyrrolidin-1-y1)-[1,3'-biazetidi ne]-lt-carboxyl ate (29h) N--, N
1..,( 1 -(azetidin-3 -yl)pyrrolidin-3 -y1)-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-d]pyrimidin-4-amine trifluoroacetate (29g) (380 mg) was dissolved in 15 mL of DCE
Date Recue/Date Received 2021-09-09 and 2 mL of DMSO, and Boc-azetidinone (210 mg, 1.22 mmol) was added, the mixture was stirred at room temperature for 10 minutes, then sodium triacetoxyborohydride (515 mg, 2.44 minol) was added, and the mixture was stirred at room temperature overnight. To the reaction system was slowly added 30 mL
of saturated sodium bicarbonate solution, and the resulted solution was extracted with 100 inL of DCM. The organic phase was washed with 100 rriL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20 : 1), to obtain tert-butyl 3-(3-(4-amino-3-(4-phenoxypheny1)-1H-pyrazo lo[3 ,4-d]pyrimidin-l-yl)pyrroli din-1-y1)-[ I ,3'-biazetidine]-1'-carboxylate (29h) (300 mg).
LCMS m/z = 583.6 [M+ l].
Step 8:
I -(1-([1,3 I-biazetidin]-3 -yl)pyrrol id in-3-y1)-3-(4-phenoxypheny1)- 111.-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate (29i) H2N iN

NH
Tert-butyl 343 -(4-am ino-3-(4-phenoxypheny1)- I H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin- I -y1)-[1,3'-biazetidine]-1t-carboxylate (291i) (300 mg, 0_51 rnmol) was dissolved in 10 mL of DCM, and 5 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 h. The reaction system was directly concentrated under reduced pressure, to obtain I -(1 -([1 ,3'-biazetidin]-3-yl)pyrrolidin-3-y1)-3-(4-phcnoxyphcnyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate (29i) (0.38 g).
LCMS m/7 = 483.4 [M+1]+.
Step 9:
5-(3-(3-(4-amino-3 -(4-phenoxypheny1)-1H-pyrazolo [3 ,4-cl] pyrimi di n-1 -Date Recue/Date Received 2021-09-09 yl)pyrrolidin-l-y1)-[ I ,Y-biazetidin]-1'-y1)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate (compound 29) N
N

1 1 -([ 1 ,3 '-bi azetidin]-3 -yl)pyrrolidin-3 -y1)-3 -(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate (29i) (0.38 g) was dissolved in 25 mL of DMSO, and 3 mL of DIPEA and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (211 mg, 0.77 mmol) were added, the reaction was stirred at 80 C for 5 h. The reaction solution was cooled to room temperature, added 50 mL of water, and extracted with 100 mL
of ethyl acetate. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethanc/methanol (v/v) = 15 : 1-5 : 1), to obtain 5-(3-(3-(4-amino-3-(4-phcnoxypheny1)-1H-pyrazo lo [3 ,4-djpyrim idin-1-yl)pyrrolidin-1 -y1)-[1,3'-biazetidin]-1'-y1)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate (compound 29) (130 mg).
lj NMR (400 MHz, DMSO-d6) 6 11.06 (s, 1H), 8.25 (s, I fi), 7.78 - 7.57 (m, 311), 7.49 - 7.35 (m, 2H), 7.27 - 7.05 (m, 514), 6.78 (d, 1H), 6.64 (dd, 1H), 5.49 - 5.31 (m, 1H), 5.05 (dd, 111), 4.14 - 3.97 (m, 211), 3.87 - 3.76 (m, 2H), 3.71 -3.61 (m, 11-1), 3.53-3.39 (m, 311), 3.23 - 3.06 (m, 3H), 2.96 - 2.70 (m, 414), 2.65 - 2.45 (m, 2H), 2.41 -2.24 (m, 2H), 2.07- 1.95 (m, 1H).
LCMS m/z = 739.3 [M+1]-1".
Example 30:
(7 S)-7-[1- [1-[142-(2,6-dioxo-3-piperidy1)-1,3-dioxo-i soindolin-5-yljazetidin-3-y1.1-4-piperidyli-4-piperidy11-2-(4-phenoxypheny1)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetate (compound 30) Date Recue/Date Received 2021-09-09 a0 , ..õ.

1_12N \µ '' N
N
HN,,_.) = = = ( . Qo 0a =

/ \
Oa\ / \
0 _ . 0 _ step. Step 2 Step 3 H2N H2N \ --0- H2N- , \ -"- H2N
\ N I N 1 N \ N
H N
\ z.___.1 HN)''''C
JNBoc 30a 30b --' 30c 30d N---(1\Neoc .
Step 4 Siep 5 0 H-,N H2N
1 \ N I \ N
N
HN\---:
N
HN L J.. 7.õ____ .._ N
\
tro NH

30e Compound 30 0 Step 1:
tert-butyl 4-14-[(7S)-3-carbamoy1-2-(4-phenoxypheny1)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimi din-7-y1]-1-piperidyl]piperidine-1-carboxylate (30b) o H2N I \
,N
N
FiN %
---CNBoc (S)-2-(4-phenoxypheny1)-7-(piperidin-4-y1)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrinndine-3-carboxamide (30a) (95% cc) (see WO 2018033853 for the synthetic method) (0.2 g, 0.48 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (0.57 g, Date Recue/Date Received 2021-09-09 2.87 mmol) were dissolved in 20 mL of chloroform, and acetic acid (0.14 g, 2.4 mmol) was added, then 1 g of 4 A molecular sieve and 1 g of anhydrous sodium sulphate were added. The mixture was warmed to 65 C and stirred for 2 Ii, sodium triacetoxyborohydride (0.61 g, 2.87 mmo1) was added, and stifling was continued at this temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 50 : 1-7 : 1), to obtain tert-butyl 4-[4-[(7S)-3-carbamoy1-2-(4-phenoxypheny1)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yli-1-piperidyl]piperidine-1-carboxylate (30b) (0.2 g, yield: 69%).
LCMS m/z = 601.3 [M+1]' Step 2:
(7S)-2-(4-phenoxypheny1)-741-(4-piperidy1)-4-piperidy1-1-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (30c) /
--H2N , N
O
N
-OH
Tert-butyl 444-[(7S)-3-carbamoy1-2-(4-phenoxypheny1)-4,5,6,7-tetrahydropyrazolo[1,5-alpyrimidin-7-y11-1-piperidyl]piperidine-l-carboxylate (30b) (0.2 g, 0.33 rnmol) was dissolved in 5 mL of dichloromethane, and 5 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 2 h.
The solvent was removed from the reaction solution under reduced pressure, and the mixed solution of 20 mL of diehloromethane and 2 mL of ethanol was added. The resulting solution was washed with 50 mL of saturated sodium bicarbonate solution, the aqueous phase was further extracted with the mixed solution of 20 mL of dichloromethane and 2 ml, ethanol, and the organic layers were combined, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain (7S)-Date Recue/Date Received 2021-09-09 2-(4-phenoxypheny1)-7-[1-(4-piperidy1)-4-piperidy1]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (30c) (0.16 g, yield: 96%).
LCMS in/z ¨ 501.3 [M-Flr.
Step 3:
tert-butyl 344-[4-[(7S)-3-earbamoy1-2-(4-phenoxypheny1)-4,5,6,7-tetrallydropyrazolo [1,5-a]pyrimidin-7-y1]-1-piperidy1]- I -pi peri dyflazetidin c-1 carboxylate (30d) /

H2N-k INBoc \ N
CN
(7S)-2-(4-phenoxypheny1)-741-(4-piperi dy1)-4-pi peridy11-4,5,6,7-to tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxarnide (30c) (0.14 g, 0.28 mmol) and tert-butyl 3-oxoazetidine-1-carboxylate (0.24 g, 1.4 minol) were dissolved in 20 naL
of chloroform, and acetic acid (0.08 g, 1.4 mmol) was added, then 1 g of 4 A
molecular sieve and 1 g of anhydrous sodium sulphate were added, and the mixture was warmed to 65 C and stirred for 2 h. Sodium triacetoxyborohydride (0.3 g, 1.4 mmol) was added, and the stirring was continued at this temperature overnight.
The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (dichloromethanc/methanol (v/v) = 50: 1-7: 1), to obtain tert-butyl 3-[4-[44(7S)-3-carbamoy1-2-(4-phenoxypheny1)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-y11-1-piperidy11-1-piperidynazetidine-l-carboxylate (30d) (0.1 g, yield: 55%).
LCMS m/z = 656.4 [M+1]+.
Step 4:
(7S)-7-[1-[1-(azeti di n-3-y1)-4-piperi dy1]-4-pi peridy1]-2-(4-phenoxypheny1)-Date Recue/Date Received 2021-09-09 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetate (30e) Qo .2N
\N
HN
V.NH
Tert-butyl 3-[4- [4-[(7 S )-3-carbam oy1-2 -(4-phenoxypheny1)- 4,5,6,7-tetrahythopyrazo lo[1,5-ajpyrimi din-7-y11-1-piperidy11-1-piperidyll azetidine-earboxylate (30d) (0.1 g, 0.15 mmol) was dissolved in 2 mL of diehloromethane, and 2 mL of trifluoroacetie acid was added, the mixture was stirred at room temperature overnight. The solvent was removed from the reaction solution under reduced pressure, to obtain (7 S)-7-[1-[1 -(azeti din-3-y1)-4-piperi dy11-4-piperidy1]-2-(4-phenoxypheny1)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-earboxamide trifluoroacetate (30e) (0.12 g).
LCMS m/z = 556.3 [M+1]'.
Step 5:
(7S)-7-[l -[1 -[1-[2-(2,6-dioxo-3-piperidy1)-1,3-dioxo-i soindolin-5-yl]azetidin-3-y1]-4-piperidy1]-4-pi peridy1]-2-(4-phenoxypheny1)-4,5 ,6,7-tetrah ydropyrazo lo [1,5 -a]pyri mi di ne-3 -carboxam ide trifluoroacetate (compound 30) SO
)1- =-=,, 0 0 N 0 (7S)-7-[1 -[1 -(azetidin-3-y1)-4-piperi dyl] -4-pi peridy11-2-(4-phenoxypheny1)-4,5 ,6,7-tetrahydropyrazolo[1,5 -a]pyrimidine-3 -earboxam ide trifluoroacetate (30e) (0.12 g) was dissolved in 3 mL of DMSO, and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (0.04 g, 0.16 mmol) and triethylamine (0.07 g, 0.67 mmol) were added, the mixture was Date Recue/Date Received 2021-09-09 warmed to 120 C and stirred for 4 h. The reaction solution was cooled to room temperature, added 10 mL of water and 20 mL of ethyl acetate, and extracted, then the solvent was removed from the organic layer under reduced pressure, and the residue was separated and purified by silica gel column chromatography (di chloromethane/methanol (v/v) = 50 : 1-10 : 1), to obtain (7 S)-7-[1 [1-[ 1-[2 -(2,6-dioxo-3 -pi peridy1)-1,3 -di oxo-i soindolin -5-yli azeti din-3-y1]-4-pi peridy11-4-piperi cly11-2-(4 -phenoxypheny1)-4,5,6,7 -tetrahydropyrazo1o[1,5-abyrimidine-carboxamide trifluoroacetate (compound 30) (45 mg).
III NMR (400 MI lz, DMSO-d6) 11.05 (s, 111), 7.64 (d, III), 7.50 (d, 211), 7.45 -7.38 (m, 2H), 7.21 - 7.14 (m, I H), 7.12- 7.02 (m, 41-I), 6.78 (d, 1H), 6.72-6.61 (m, 21-1), 5.05 (dd, 1H), 4.16 - 3.96 (m, 3H), 3.87 - 3.73 (m, 2H), 3.35 -3.28 (m, 1H), 2.97 -2.78 (m, 31-1), 2.58- 2.52 (in, 11H), 2.10- 1.73 (m, 8H), 1.72 - 1.45 (in, 4H).
LCMS m/z = 812.4 [M-F-1]+.
Example 31:
(7S)-7-114141-[2- (2,6-d ioxo-3-p iperidy1)-1,3-d ioxo-i soi ndolin -5-yl]
azetid in-3-yl] azetid in-3-y1]-4-piperidy1]-2-(4-phenoxypheny1)-4,5,6,7-tetrahydropyrazolo[1,5-ajpyrimidine-3-carboxamide trifluoroacetate (compound 31) H 1µ41, ;12,1,1 HNj Date Recue/Date Received 2021-09-09 Q Q Q Q
0 . 0 .
0 _ ,,, ¨ Step 1 Slcp 2 _.. 0 - s, t ... 1 ' -i . ,2õ......k H2N" \ H2N - \ 112N \
FINL) c____,µ ,,____., 309 319 31b CZ Q
s o.õ4 0 --3: Si,v5 _õ
1-12N)5[N H2NA-y\N
N
HN HN N
--"' \õ..N.--..õ---,õ __.) =,,/Th OH
ZN___r0 31d t: ompound 31 0 Step 1:
tert-butyl 3-[44(7S)-3-carbamoyl-2-(4-phenoxyphenyl)-4,5,6,7-tetrah ydropyrazolo [1,5-a]pyrimi din-7-y11- 1-pi peri dyllazetidine- I -carboxylate (31a) o H2N , \
I N
N
HN
CN--,--N
\,,NEico (S)-2-(4-phcnoxyphcny1)-7-(piperidin-4-y1)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (30a) (95% ee) (see WO 2018033853 for the synthetic method) (0.2 g, 0.48 mmol) and tert-butyl 3-oxoazetidine- 1 -carboxylate (0.41 g, 2.40 mmol) were dissolved in 20 mL of chloroform, and acetic acid (0.14 g, 2.4 mmol) was added, then I g of 4 A molecular sieve and 1 g of anhydrous sodium sulphate were added. The mixture was warmed to 65 C and stirred for 2 h, sodium triacetoxyborohydride (0.61 g, 2.87 mmol) was added, and stirring was continued at this temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica Date Recue/Date Received 2021-09-09 gel column chromatography (dichloromethane/methanol (v/v) = 50 : 1-7 : I), to obtain tert-butyl 3 -[4-[(7 S)-3 -carbamoy1-2-(4-phenoxypheny1)-4,5,6,7-tetrahydropyrazolo [1,5-a]pyrimidin-7-ylj- 1-piperidyliaze tidi ne-l-carboxylate (31a) (0.25 g, yield: 91%).
LCMS m/z = 573.4 [M 1]'.
Step 2:
(7S)-7- [1- (azetidin-3-y1)-4-piperidyl] -2-(4-phenoxypheny1)-4,5,6,7-tetrahydropyrazo lo [1,5- ajpyrimi din e-3 -earboxami de (31b) \,,NH
Tert-butyl 3-[4-[(7S)-3-carbamoy1-2-(4-phenoxypheny1)-4,5,6,7-tetrahydropyrazolo[1,5-alpyrimi din-7-y1]- 1-pi peri dy I] azeti di rie- I -carboxylate (31a) (0.25 g, 0.44 mmol) was dissolved in 5 mL of dichloromethane, and 5 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 2 h.
The solvent was removed from the reaction solution under reduced pressure, and the is mixed solution of 20 mL of dichloromethane and 2 mL of ethanol was added. The resulting solution was washed with 50 itiL of saturated sodium bicarbonate solution, the aqueous phase was further extracted with the mixed solution of 20 mL of dichloromethane and 2 mL ethanol, and the organic layers were combined, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain (7S)-7-[1-(azetidin-3-y1)-4-piperidy1]-2-(4-phenoxyphenyl )-4,5,6,7-tetrahydropyrazolo[1,5-alpyrimi dine-3-carboxam i de (31b) (0.19 g, yield:
92%).
LCMS m/z 473.4 [M
Step 3:
tert-butyl 34344-[(7 S)-3-earb amoy1-2-(4-phenoxypheny1)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-y11-1-piperidyl]azetidin-l-yflazetidine-1-carboxylate (31c) Date Recue/Date Received 2021-09-09 Q

1-121\1)CN
1-1N, \,NBoc (7 S)-7-[1-(azetidin-3 -y1)-4-pi peridyl} -2 -(4-phenoxyphenyI)-4,5,6,7-tetrahydropyrazolo [1,5-ajpyrimidine-3 -carboxamide (3 lb) (0.19 g, 0.40 mmol) and tert-butyl 3-oxoazetidine-1-carboxylate (0.34 g, 2.01 mmol) were dissolved in 20 mL
of chloroform, and acetic acid (0.12 g, 2.01 mmol) was added, then 1 g of 4 A
molecular sieve and 1 g of anhydrous sodium sulphate were added, and the mixture was warmed to 65 C and stirred for 2 h. Sodium triacetoxyborohydride (0.43 g, 2.01 mmol) was added, and the stin-ing was continued at this temperature overnight.
The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) ¨ 50: 1-7 : 1), to obtain tert-butyl 3- [3- [(7 S)-3-carbamoy1-2 -(4-phenoxypheny1)-4,5,6,7-tetrahydropyrazolo a]pyrimidin-7-.ylj- (31c) (0. 14 g, yield: 46%).
LCMS m/z = 628.3 [M
Step 4:
(75)-7-[1 -[1- (azetidin-3 -ypazetidin-3-y11-4-piperidy1]-2-(4- phenoxyph eny1)-4,5,6,7-tetrahydropyrazo10 [1,5-a]pyrimidine-3-carboxamide (31d) Q

N
HN
Date Recue/Date Received 2021-09-09 Tert-butyl 343- [4-[(7S)-3-carbamoy1-2-(4-phenoxypheny1)-4,5,6,7-tetrahydropyrazo lo [1,5-a]pyrimidin-7-yli- 1-piperidy l]azetidin-l-yl]azetidine-1-carboxylate (31c) (0.14 g, 0.22 mmol) was dissolved in 5 mL of dichloromethane, and 5 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 2 h. The solvent was removed from the reaction solution under reduced pressure, and the mixed solution of 20 rriL of dichloromethane and 2 nit of ethanol was added. The resulting solution was washed with 50 mL of saturated sodium bicarbonate solution, the aqueous phase was further extracted with the mixed solution of 20 mL of dichloromethane and 2 mL ethanol, and the organic layers were combined, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain (7S)-7-[1-[1-(azetidin-3-yl)azetidin-3-y1]-4-piperidyli-2-(4-phenoxypheny1)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (31d) (0.10 g, yield: 85%).
LCMS miz = 528.3 [M+1]+.
Step 5:
(7S)-7-[1-[1-[142-(2,6-dioxo-3-piperidy1)-1,3-dioxo-isoindolin-5-yliazetidin-3-yl]azetidin-3-y1]-4-piperidyli-2-(4-phenoxypheny1)-4,5,6,7-tetrahydropyrazolo[1,5-ajpyrimidine-3-carboxamide trifluoroacetate (compound 31) FINµ.
0 a H
_t_Nyo (7S)-7-[1-[1-(azetidin-3-yl)azetidin-3-y1]-4-piperidy1]-2-(4-phenoxypheny1)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (31d) (0.03 g, 0.057 mmol) was dissolved in 3 mL of DMSO, and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (0.019 g, 0.068 mmol) and triethylamine (0.022 g, 0.17 mmol) were added, the mixture was warmed to 120 C and stirred for 4 h. The reaction solution was cooled to room Date Recue/Date Received 2021-09-09 temperature, added 10 mL of water, and extracted with 20 mL of ethyl acetate.
The solvent was removed from the organic layer under reduced pressure, and the residue was passed through Pre-HPLC (instrument and preparative column: using Glison (iX-281 to prepare the liquid phase, preparative column model: Sunfire C18, 5 11M, inner diameter x length = 30 mmx150 mm). Preparation method: The crude product was dissolved with methanol and dimethyl sulphoxide, and filtered with 0.45 pm filter membrane, to prepare into a sample solution. Mobile phase system:
acetonitrile/water (containing 0.1% TFA). Gradient elution method: gradient elution with acetonitrile from 5% to 60% (elution time: 15 min), the reaction system was lyophilized to obtain (7S)-7-[ l-[ I -[1-[2-(2,6-dioxo-3-piperidy1)- I ,3-dioxo-isoindolin-5-yl]azetidin-3-yliazetidin-3-y1]-4-piperidy1]-2-(4-phenoxypheny1)-4,5,6,7-tetrahydropyrazolo[1,5-alpyrimidine-3-carboxamide trifluoroacetate (compound 31) (15 mg).
11-1 NMR (400 MHz, DMSO-d6) 6 1 LOS (s, 1H), 7.68 (d, 1H), 753 - 7.47 (m, 2H), 7.45 - 7.38 (m, 2H), 7.21 - 7.14 (m, 111), 7.13 - 6.98 (m, 4H), 6.96 -6.44 (m, 311), 5.06 (dd, 111), 4.22 - 3.60 (m, 1111), 3.45 - 3.26 (in, 411), 2.97 -2.64 (m, 311), 2.63 -2.45 (m, 2H), 2.34 - 2.15 (in, 1H), 2.12- 1.50 (m, 7H).
LCMS m/z ¨ 784.3 [M+1]+.
Example 32:
5-(3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-d] pyrimi di n-1 -yI)-[ I ,4'-bipiperi din] -11-ypazetidi n- -y1)-2-(2,6-dioxopiperidin-3-y1)-6-fluoroi soindoline-1,3-cli one (compound 32) H2N \ IN
o Oil 0 N=-A, Step 0 '1\1-N10 83) Cornpoimd 32 I. --(1T-(azetidin-3-y1)41,4'-bipiperidin]-4-0-3-(4-phcnoxypheny1)- I H-Date Recue/Date Received 2021-09-09 pyrazolo[3,4-d]pyrimidin-4-amine (8b) (290 mg, 0.55 mmol) was dissolved in 10 mL
of DMSO, and 1 mL of DIPEA and 2-(2,6-dioxopiperidin-3-y1)-5,6-difluoroisoindoline-1,3-dione (21b) (150 mg, 0.51 ininol) were added, the mixture was stirred in external bath at 80 C for 5 h. The reaction solution was cooled to room temperature, added 50 mL of water, and extracted with 100 mL of ethyl acetate.
The organic phase was washed with 50 niL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 15 : 1), to obtain 5-(3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-l-y1)41,4'-bipiperidini-l'-yl)azetidin-1-y1)-2-(2,6-dioxopiperidin-3-y1)-6-fluoroisoindoline-1,3-dione (compound 32) (150 mg, yield: 34%).
'H NMR (400 MHz, DMSO-d6) 6 11.06 (s, 1H), 8.23 (s, 1H), 7.70- 7.63 (m, 21-1), 7.60 (d, 1H), 7A8 - 7.39 (m, 2H), 7.23 - 7.09 (m, 5H), 6.92 (d, 1H), 5.07 (dd, 1H), 4.69 - 4.57 (m, 1H), 4.28 - 4.18 (in, 2H), 4.02 - 3.90 (n, 2H), 3.30 -3.21 (n, 111), 3.07 - 2.96 (m, 2H), 2.94 - 2.80 (rn, 3H), 2.69- 2.52 (n, 211), 2.41 -2.27 (n, 3H), 2.24 -2.08 (n, 2H), 2.07 - 1.96 (in, 1H), 1.96- 1.70 (in, 6H), 1.56- 1.39 (m, 214).
LCMS m/z = 799.3 [M+1]+.
Example 33:
4-[8-amino-3- [(2S)-1-[1-[142-(2,6-dioxo-3-piperidy1)-1,3-dioxo-isoindolin-5-yl]azetidin-3-y1]-4-piperidyl]pyrrolidin-2-yl] imidazo[1,5-a]pyrazin-l-yll-N-(2-pyridyl)benzamide (compound 33) z N

NH

Date Recue/Date Received 2021-09-09 0, Ckr, ON a ,,,,, rrN-% C.,_,N,Boc slep 2 , eTh.:4--\
,,NH s(ep , , -r7'NCiN c______, NI2 L-- N.,,r)-- ____ _--(30c NH2 / \ NH, '.- N N, --'NH2 /
/.-_, N N N N

33a 33E. 33c 33c4 Slcp _____________ NH2 N NH NH

33e Compound 33 0 Step 1:
tert-butyl 4- [(2S)-248-amino-144-(2-pyridylcarbamoyl)phenyljimidazo[1,5-a]pyrazin-3-yl]pyn-olidin-1-yl]piperidine-1-carboxylate (33b) a _ -r--N--- 0 N ---- N 'Boe N

(S)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-y1)-N-(pyridin-2-y1)benzarnide (33a) (0.500 g, 1.25 mmol) was dissolved in 5 mL of 1,2-dichloroethane, and N-tert-butoxycarbony1-4-piperidone (0.374 g, 1.88 mmol) and glacial acetic acid (0.150 g, 2.50 mmol) were added. Upon completion of the addition, the reaction was carried out at 65 C for 3 h, cooled to room temperature, and sodium triacetoxyborohydride (0.531 g, 2.50 mmol) was added. Upon completion of the addition, the reaction was carried out at room temperature overnight. To the reaction system was added dropwise saturated sodium bicarbonate solution to adjust the pH
to 9-10, and same was concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 100 : 0-19 : 1), to obtain tert-butyl 4-[(2S)-2-[8-Date Recue/Date Received 2021-09-09 amino- I 44-(2-pyridylcarbarnoyl)phenyl]i rnidazo [1,5 -a]pyrazin-3 -yl}pyrrolidin-1-ylipiperidine- 1 -carboxylate (33b) (0.340 g, yield: 47%).
LCMS in/z ¨ 583.3 [M-Fl Step 2:
448-amino-3-[(2S)-1-(4-piperidyl)pyrrol imidazo[1,5-a]pyrazin- 1 -y1 j-N-(2-pyridyl )benzain ide (33c) OH
ON
N
N --Tert-butyl 4- [(2S)-2- [8-amino-144-(2-pyridylcarbarnoyl)phenyljimidazo[1 ,5-alpyrazin-3-ylipyrrol idin-1-yl]piperidine-l-earboxylate (33b) (0.340 g, 0.583 mmol) was dissolved in 2 m1, of dichlorom ethane, and S m1, of 4 N dioxane hydrochloride solution was added, the mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, and then to the residue was added nil, of di chloromethane. The pH was adjusted to 9-10 with saturated sodium bicarbonate solution. The liquid separation was conducted, and the organic layer was 15 dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichlorornethane/rnethanol (v/v) = 19 : 0-I: 1), to obtain 448-ainino-3-[(2S)-1-(4-piperidyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-l-yll-N-(2-pyridyl)benzamide (33c) (0.206 g, yield: 73%).
20 LCMS m/z = 483.3 [M+1]+.
Step 3:
tert-butyl 344-[(2S)-248-amino-114-(2-pyridylcarbamoyl)phenyllimidazo [1,5-a]pyrazin-3 -yl]pyrrol idin-l-yl] -1 -piperidyliazetidine-1-carboxylate (33d) Date Recue/Date Received 2021-09-09 N o N
Boc 448-amino-3-[(2S)-1-(4-piperidyl)pyrrolidin-2-yl] irnidazo [1,5 -alpyrazin-1 -y1j-N-(2-pyridyl)benzamide (33c) (0.200 g, 0.414 mmol) was dissolved in 5 mL of 1,2-dichloroethane, and 2 mL of dimethyl sulphoxide was added, then tert-butyl 3-oxoazetidine-1 -carboxylate (0.106g. 0.622 mmol) and glacial acetic acid (0.0498 g, 0.829 mmol) were added. Upon completion of the addition, the reaction was canied out at 65 C for 3 h, cooled to room temperature, and sodium triacetoxyborohydride (0.176 g, 0.829 mmol) was added. Upon completion of the addition, the reaction was carried out at room temperature for 2 h. To the reaction system was added dropwise saturated sodium bicarbonate solution to adjust the pH to 9-10, and same was concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) =
100 0-19 :
1), to obtain tert-butyl 3-[4- [(2S)-2-[8- am i no-14442-pyridylcarbamoyl)phenyll imidazo [1,5-a]pymzin-3-yl]pyrrolidin- 1-y1]-1 -piperidyflazetidine- 1-carboxylate (33d) (0.090 g, yield: 34%).
Step 4:
448-amino-34(2S)-141-(azetidin-3-y1)-4-piperidylipyrrolidin-2-yl] imidazo [1 ,5-a] pyrazin-1 -yI]-N-(2 -pyridy 1)benzamide (33e) cL
N

Tert-butyl 3444(2S)-248-amino-144-(2-pyridylcarbamoyl)phenyllimidazo[1,5-a]pyrazin-3-yl]pyrrolidin-1-y1]-1 -Date Recue/Date Received 2021-09-09 piperidyflazetidine- 1 -carboxylate (33d) (0.090 g, 0.14 mmol) was dissolved in 2 mL
of dichloromethane, and 5 mL of 4 N dioxane hydrochloride solution was added, and the mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, and then to the residue was added 20 mL
of dichloromethane. The pH was adjusted to 9-10 with saturated sodium bicarbonate solution. The liquid separation was conducted, and the organic layer was dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain 4-[8-amino-3- [(2S)- 1-[1-(azetidin-3-y1)-4-piperidyljpyrrolidin-2-yl] im idazo [1,5-ajpyrazin- 1 -yli-N-(2-pyridyl)benzamide (33e) (0.076 g, yield: > 99%).
LCMS m/z = 538.3 [M+1] .
Step 5:
4-[8-amino-3- [(2S)-1-[1- [1-[2-(2,6-dioxo-3-piperidy1)-1,3-dioxo-i soi ndo li n-5-yll azetidin-3-y1]-4-piperidyllpyrrolidin-2-yl] imidazo r1,5-ajpyrazin- 1-yll-N-(2-pyridyl)benzamid e (compound 33) CN
N N

NH NH

4-[8-amino-3-[(2S)-1-[1-(azetidin-3-y1)-4-piperidyl]pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-l-y11-N-(2-pyridyl)benzamide (33e) (0.076 g, 0.141 mrnol) was dissolved in 2 mL of dimethyl sulphoxide, and 2-(2,6-dioxopiperidin-3-y1)-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (0.0468 g, 0.170 mmol) and diisopropylethylamine (0.0913 g, 0.707 mmol) were added.
Upon completion of the addition, the reaction was carried out at 90 C for 2 h. The reaction solution was cooled to room temperature, to which 10 mL of water was slowly added dropwise, and filtered. The filter cake was dissolved with 20 mL of dichloromethane, then washed with 5 mL of saturated sodium chloride solution. The liquid separation was conducted, and the organic layer was dried over anhydrous sodium sulphate, and Date Recue/Date Received 2021-09-09 concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) =

100 : 0-19 : 1), to obtain 448-amino-3 -R2S)-1-[1-[142-(2,6-dioxo-3-piperi dy1)-1,3-di oxo -iso indol in -5-yl jazeti di n -3-y1I-4 -piperidyl jpytTol idin-2-y1 jimi dazo [1,5-a]pyrazin-l-y1]-N-(2-pyridyl)benzamide (compound 33) (0.055 g, yield: 49%).
11-1 NMR (400 MHz, CDC13) 6 8.53 - 8.37 (in, 2H), 8.20 - 7.98 (in, 3H), 7.83 -7.75 (m, 1H), 7.73 - 7.56 (m, 2H), 7.51 - 7.38 (m, 1H), 7.29 - 7.21 (m, 1H), 7.16 -7.05 (m, 21-1), 6.80 - 6.71 (rn, 1H), 6.48 - 6.40 (m, 1H), 5.50 (brs, 2H), 4.99 - 4.89 (m, 111), 4.53 -4.41 (m, 111.), 4.13 - 4.02 (m, HI), 3.99 - 3.83 (m, 110, 3.82 -3.32 (m, 4H), 2.97 - 2.58 (m, 6H), 2.56 - 2.30 (in, 2H), 2.25 - 1.55 (m, 11H).
LCMS m/z = 794.3 [M+1]'.
Example 34:
5-[144- [(3R)-344 -amino-3-(4-phenoxyphenyl)pyrazolo [3,4-d]pyrimidin-l-yll-1 -piperidylicyc lohexyljazetid in- 3-yljoxy-2-(2,6- dioxo-3-piperi dyl) iso in doline-1,3-dione (compound 34-a) 5- [1 14- [(3 R )-344-arnino-3-(4-phenoxyphenyl)pyrazolo [3,4-d]pyrim 1 -piperidy I]cyclohexyliazeti din -3-yl]oxy-2-(2,6- dioxo-3-piperi dyl) isoin doline-1,3-dione (compound 34-b) 0 0 -J \/
N
N N
(Cis) 0 'T,s4N1H ¨N 'AP 0 u.
_N
H2N, N, H N

N
Date Recue/Date Received 2021-09-09 oo p p P 0 H
0 * N
,),LN....C...) Step I 0 / N13 Step 2 -N N
.,..._ , ,N
k .
H2N); N

H / \ /
2NN H2r4 N
N--/ Nrr-/ N=J
28a 34a 346 Step 5 .-0 ,0 t 0 Siep 3 Ej --rC) 0 SteP 4 _____ I i 0 N ¨.- BouN N _I( HN

34c 34d 34e 9 _/0 N N N
(cm) 0 NH
0 N'Cl(N1-1 ftran,) ¨N

N- NI I I2N 1\1"-C
.----I
Compound 34-a and Compound 34-b Step 1:
1-[(3R)- 1 - ( 1,4-dioxaspiro [4.5]decan-8-y1)-3-p iperidyli-3-(4-phenoxyphenyl)pyrazolo[3,4-djpyrimidin-4-amine (34a) N

N, ...0 --- N
/ \ N H2N
NI,-7---/
(R)-3-(4-phcnoxypheny1)-1-(piperi din-3-yI)-1H-pyrazo lo [3,4-dipyrim i din-4-amine (28a) (1.00 g, 2.59 mmol) was dissolved in 10 rnL of chloroform, and 1,4-dioxaspiro[4.5]decan-8-one (0.606 g, 3.88 mmol) and glacial acetic acid (0.311 g, 5.18 mmol) were added. Upon completion of the addition, the reaction was carried out at 70 C for 3 h, then cooled to room temperature, and sodium triacetoxyborohydride (1.10 g, 5.18 mmol) was added. Upon completion of the Date Recue/Date Received 2021-09-09 addition, the reaction was carried out at room temperature for 2 h. To the reaction system was added dropwise saturated sodium bicarbonate solution to adjust the pH
to 9-10, and same was concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 100 : 0-19 : 1), to obtain 1-[(3R)-1-(1,4-diox aspiro[4.5] decan-8-y1)-3-piperidy1]-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine (34a) (0.530 g, yield: 39%).
LCMS m/z = 527.3 [M+1] .
Step 2:
4-[(3R)-344-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-y1]-1-piperidyl]cyclohexanone (34b) o N, N
\ N

1-[(3R)-1-(1,4-dioxaspiro[4.5]decan-8-y1)-3-piperidy1]-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine (34a) (0.530 g, 1.01 mmol) was is dissolved in 5 ml. of tetrahydrofuran, and 5 ml. of 4 N hydrochloric acid aqueous solution was added, the mixture was stin-ed at room temperature for I h. The reaction solution was concentrated, and then to the residue was added 20 mL of clichloromethane. The pH was adjusted to 9-10 with saturated sodium bicarbonate solution. The liquid separation was conducted, the aqueous layer was further extracted with 20 mL of dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain 4-[(3R)-3-[4-am ino-3-(4-phenoxyphenyl)pyrazolo [3 ,4-d] pyrim idin -1-yI]-1-pipe ri dyl lcycl ohexanone (34b) (0.480 g, yield: 99%).
Step 3:
tert-butyl 3 42-(2,6-dioxo-3-p iperi dy1)-1,3 dioxo-isoindol in-5 -yl]oxyazetidine-1-carboxylate (34d) Date Recue/Date Received 2021-09-09 N¨

Bod NH

2-(2,6-dioxopiperidin-3-y1)-5-hydroxyl isoindol ine-1,3-di one (34c) (see US20180099940 for the synthetic method) (1.00 g, 3.65 mmol) was dissolved in mL of DMF, and tert-butyl 3-((methylsulfonypoxy)azetidine-1-carboxylate (1.01 g, 4.01 mmol) and cesium carbonate (2.38 g, 7.29 mmol) were added. Upon completion of the addition, the reaction was carried out at 110 C under microwave for 2 h. The reaction solution was cooled to room temperature, and 20 mL of water and 50 mL
of ethyl acetate were added. The liquid separation was conducted, the aqueous layer was further extracted with 20 mL of ethyl acetate, and the organic layers were combined.
The ()runic phase was washed with 20 mL of saturated sodium chloride, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4: 1-1 : 1), to obtain tert-butyl 342-(2,6-dioxo-3-p iperidy1)-1,3-dioxo-iso indol in-5-yl]oxyazetidine-1- carboxylate (34d) (0.670 g, is yield: 43%).
Step 4:
5-(azetidin-3-yloxy)-2-(2 ,6-di oxo-3-pi peri dyl)i soindol ine-1,3-di on e hydrochloride (34e) I
HN¨

Tert-butyl 3-[2-(2,6-dioxo-3-piperidyI)-1,3-dioxo-isoindolin-5-yl]oxyazetidine-1-carboxylate (34d) (0.670 g, 1.56 mmol) was dissolved in 2 mL of dichloromethane, and 10 mL of 2 N ethyl acetate hydrochloride solution was added, the mixture was stirred at room temperature for 2 h. The reaction solution was filtered, and the filter cake was collected, and dried to obtain 5-(azetidin-3-yloxy)-2-(2,6-dioxo-3-piperidypisoindoline-1,3-dione hydrochloride (34e) (0.484 g).
Date Recue/Date Received 2021-09-09 LCMS m/z = 330.1 [M+1].
Step 5:
54144- [(3R)-344-amino-3 -(4-phenoxyphenyl)pyrazolo [3 ,4-d]pyrim idin-1 -y1]-1-piperidy 1 jcyclohexyl jazeti din-3-y1 joxy-2-(2,6- dioxo-3-piperi dyl )iso in dol in e-1,3-dione (compound 34-a) 5-[1 -[4- [(3 R)-344-amino-3 -(4-phenoxyphenyl)pyrazolo [3 ,4-d] py rimidin-1 -y1 1-piperidy l]cyclohexyllazetidin-3-ylloxy-2-(2,6- dioxo-3-piperi dyl) isoindolin e-1,3-dione (compound 34-b) \-2 0 41k N
_N 0 Z-r14_:ZH
H2N ,N

N N N
54azetidin-3 -yloxy)-2-(2 ,6-dioxo-3 -piperidyflisoindol ine-1,3 dione hydrochloride (34e) (0.066 g) was dissolved in 2 mL of anhydrous methanol, and sodium bicarbonate solid (0.020 g, 0.24 mmol) was added. The mixture was stirred at room temperature for 20 minutes, and filtered, the filter cake was washed with 1 nil, of methanol, and the filtrate was combined and concentrated, then the residue was dissolved in 2 mL of chloroform. 0.5 triL of DMSO, glacial acetic acid (0.022 g, 0.36 mmol) and 4-[(3R)-344-amino-344-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin--y11-1-piperidyl]cyclohexanone (34b) (0.13 g, 0.27 mmol) were added. Upon completion of the addition, the reaction was stirred at 70 C for 5 h, and cooled to room temperature. Sodium triacetoxyborohydride (0.077 g, 0.36 mmol) was added, and the reaction was carried out at room temperature overnight. To the reaction system was added dropwise saturated sodium bicarbonate solution to adjust the pH
to 9-10, and 20 mL of dichloromethane was added. The liquid separation was conducted, the aqueous layer was further extracted with 10 mL of dichloromethane once, and the organic layers were combined, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) =

100 : 0-6 : 1), to obtain two pure products, 54144-[(3R)-344-amino-3-(4-phenoxyphenyppyrazolo[3,4-d]pyrimidin-l-y1]-1-piperidyljcyclohexyl]azeti din-3 -Date Recue/Date Received 2021-09-09 yljoxy-2-(2,6-dioxo-3-piperidypisoindoline-1,3-dione (compound 34-a) (23 mg) and 541-[4-[(3R)-3- [4-amino-3-(4-phenoxyph enyl)pyrazolo [3 ,4-d]pyrimidin-l-y1]-piperidyl]cyclohexyl} azeti din-3-ylloxy-2-(2,6-dioxo-3 -piperidypi soindoline-1,3-dione (compound 34-b) (25 111g).
Compound 34-a: (developing solvent: dichloromethane/methanol = 10 : 1, Rf value ¨ 0.45) 11-1 NMR (400 MHz, CDC13) 6 8.79 (s, 1H), 8.39 (s, 1H), 7.77 (d, 1H), 7.67 -7.61 (in, 2H), 7.42- 7.34 (m, 2H), 7.21 -7.12 (in, 4H), 7.11 - 7.05 (m, 3H), 5.64 (brs, 211), 5.54 - 5.37 (in, 111), 4.95 (dd, 111), 4.88 - 4.79 (in, 111), 3.89 -3.77 (in, 211), 3.54 -3.40 (in, 1H), 3.36 - 3.15 (in, 2H), 3.12- 3.01 (m, 2H), 2.95 - 2.65 (in, 5H), 2.46 -2.40 (in, 1H), 2.28 - 2.09 (m, 4H), 2.06 - 1.95 (in, 3H), 1.92 - 1.72 (in, 5H), 1.49 -1.44 (in, 1H).
LCMS m/z = 796.3 [M-F-1]+.
Compound 34-b: (developing solvent: diehloromethane/methanol = 10 : 1, Rf value = 0.35) 11-1 NMR (400 MHz, CDC13) 6 8.77 (s, 1H), 8.37 (s, 111), 7.78 (d, 1H), 7.66 -7.60 (in, 2H), 7.42 - 7.36 (in, 2H), 7.20 - 7.05 (in, 7H), 5.60 (brs, 2H), 5.32 - 5.16 (in, 1H), 4.99 - 4.88 (in, 2H), 3.99 - 3.87 (m, 2H), 3.42 - 3.00 (m, 5H), 2.94 -2.62 (in, 5H), 2.58 -2.46 (in, 1H), 2.27 - 2.06 (in, 8H), 1.98 - 1.88 (in, 2H), 1.53 -1.44 (in, 1H), 1.20- 1.11 (in, 2H).
LCMS m/z = 796.4 [M 1]+.
Example 35 54444- [4- [4-amino-3 [3,4- d]pyrimid in-l-y1]-1-piperidyljpyrazol-1 -y1]-1-piperidy11-2-(2,6-dioxo-3-piperidypiso indoline-1,3-dione (compound 35) /=N
,N.
t(µj \ N 0 Date Recue/Date Received 2021-09-09 ,N_OH Siep 1 siep H,N_ON \ H2N N
N=Z
N=/
in 35a _N
µ1\1 -"CNN St"' /
\ N H2N N

N=7 N=1 0 NizjH
35d Compound 35 Step 1:
tert-butyl 4444444-amino-3-(4-phenoxypheny1)pyrazolo[3,4-d]pyrimidin-1-yll -1-piperidyl]pyrazol-1-yl]piperidine-1-carboxylate (35a) ii\r-C\N"-C\N
=-= N --E3oc H2N = \ N
N=i Tert-butyl 4-(4-iodopyrazol- I -yl)piperidine-l-carboxylate (0.500 g, 1.33 mmol) was dissolved in 2 mL of dimethyl sulphoxide, and 3-(4-phenoxypheny1)-1-(piperidin-4-y1)-11-1-pyrazolo [3,4-d]pyrimidin-4-amine ( 1 a) (see J. Med.
Chem. 2015, 58, 9625-9638 for the synthetic method) (0.615 g, 1.59 mmol), L-proline (0.0610g.
to 0.530 mmol) and potassium carbonate (0.550 g, 3.98 mmol) were successively added.
Nitrogen replacement was carried out three times, and cuprous iodide (0.0505 g, 0.265 mmol) was added. Upon completion of the addition, the mixture was heated to 100 C and reacted for 5 h. The reaction solution was cooled to room temperature, and mL of water and 10 mL of ethyl acetate were added. The liquid separation was conducted, the aqueous layer was further extracted with 10 mL of ethyl acetate, and the organic layers were combined. The organic phase was washed with 10 mL of saturated sodium chloride, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 100 : 0-19 : 1), Date Recue/Date Received 2021-09-09 to obtain tert-butyl 444444444-amino-3 -(4-phenoxyphenyl)pyrazolo [3,4-d]pyrim idin-l-yl] -1 -p iperidyl]pyrazol-1 -yl]piperidine -1 -carboxylate (35a) (0.0730 g, yield: 9%).
Step 2:
3 -(4-phenoxypheny1)-1-[ 1 4 1-(4-pi peridyl)pyrazol-4-y1]-4-piperidyljpyrazolo[3,4-d]pyrimidin-4-amine (35b) N, H2N \ N
N=Z
Tert-butyl 444444444-amino-3 -(4 -phenoxyphenyl )pyrazol o[3 ,4 -dlpyrimid in-1 -y11-1-piperidyl] pyrazol-1 -ylipiperidine-l-earboxylate (35a) (0.0730 g, 0.115 mrnol) was dissolved in 2 mL of dichloromethane, and 5 mL of 4 N ethyl acetate hydrochloride solution was added, the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated, then to the crude product was added mL of dichloromethane, and the pH was adjusted to 9-10 with saturated sodium bicarbonate solution. The liquid separation was conducted, the organic layer was is dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain 3-(4-phenoxyphe ny1)-1 -[1-[1-(4-piperidyl)pyrazol -4-y1]-4-pipe ridy lipyrazolo[3,4-d]pyrim idin -4-am ine (35b) (0.0615g, yield: > 99%).
Step 3:
54444- [4- [4-arnino-3-(4-phenoxyphenyl)pyrazolo [3,4-d]pyrimid in-1-y1]-1-piperidyljpyrazol-1-y1]-1-piperidy1]-2-(2,6-dioxo-3-piperidypisoindoline-1,3-dione (compound 35) 'N-GN-CM ON

3-(4-phenoxypheny1)-1-[1-[1-(4-pi peri dyl)pyrazol-4-y1]-4-Date Recue/Date Received 2021-09-09 piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (35b) (0.0600 g, 0.112 mmol) was dissolved in 2 mL of dimethyl sulphoxide, and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (0.0402 g, 0.146 mmol) and diisopropylethylamine (0.0724g. 0.560 mmol) were added.
Upon completion of the addition, the reaction was stirred at 90 C for 2 h. The reaction solution was cooled to room temperature, added 10 mL of water, and filtered.
The filter cake was dissolved with 20 mL of diehloromethane, then washed with 5 mL
of saturated sodium chloride, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 100 : 0-92 : 8), to obtain 544-[41444-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin- 1 -y11-1-piperidy ljpyrazol-1 -y11-1 -p iperidy1]-2-(2,6-dioxo-3 -piperidy flisoindol ine-1,3-dione (compound 35) (0.0350 g, yield: 40%).
11-1 NMR (400 MHz, CDC13) 8 8.36 (s, 1H), 8.23 (s, 1H), 7.73 - 7.69 (m, 11-1), 7.68 - 7.60 (m, 2H), 7.43 -7.36 (m, 2H), 7.33 (d, 1H), 7.29 - 7.26 (m, 2H), 7.21 -7.05 (in, 6H), 6.15 (brs, 211), 4.99 - 4.83 (in, 21-1), 4.36 - 4.28 (m, 1H), 4.12 -4.02 (m, 211), 3.58 - 3.49 (in, 2H), 3.23 - 3.12 (in, 2H), 2.95 - 2.67 (m, 5H), 2.63 - 2.50 (in, 2H), 2.30 - 2.21 (m, 2H), 2.18 - 2.05 (m, 51-1).
LCMS m/z = 792.3 [M+
Example 36 5-[ I -[4- [4-[4-amino-3 -(4-phenoxyphenyl)pyrazolo [3 ,4-dipyrimid in- 1 -y11-I -piperidyl]cyclohexyljazetidin-3-yl]oxy-2-(2,6-dioxo-3-piperidyl)isoindo line-1,3-dione (compound 36-a) 5-[144- [444-amino-3 -(4-phenoxyphenyl)pyrazolo [3 ,4-djpyrimidin-l-yl] -1-p iperidyl] cyclohexyl]azetidin-3 -y Ijoxy-2-(2,6-dioxo-3 -piperidyl)iso indo line-1,3 -dione trifluoroacetate (compound 36-b) HN

H2N / \N 0 fN1-1 Date Recue/Date Received 2021-09-09 ¨1 Step EY
St:P N_ Scep 3 N

H2N¨hi N
N=I H2N \ N
la 36a Q(cis)N0 0_ r fans -N¨C1 Compound 36-a and Compound 36-b Step I:
14 1 -(1,4-dioxaspiro [4.5 jdecan-8-y1)-4-piperidy1]-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine (36a) N
\ hi2N N
N=
3-(4-phenoxypheny1)-1-(piperid in-4 -y1)-1H -pyrazo lo [3,4-d ]pyrimid in-4 -amine (la) (see 3. Med. Chem. 2015, 58, 9625-9638 for the synthetic method) (1.00 g, 2.59 mmol) was dissolved in 5 mL of 1,2-dichloroethane, and 1,4-dioxaspiro[4.5]decan-8-one (0.606 g, 3.88 mmol) and glacial acetic acid (0311 g, 5.18 mmol) was added.
Upon completion of the addition, the reaction was stirred at 65 C for 3 h, then cooled to room temperature, and sodium triacetoxyborohydride (1.10 g, 5.18 mmol) was added. Upon completion of the addition, the reaction was carried out at room temperature for 2 h. To the reaction solution was added dropwise saturated sodium bicarbonate solution to adjust the pH to 9-10, and same was concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) 100 : 0-19: 1), to obtain 1-[l -(1,4 -dioxaspiro [4 .5]decan-8-y1)-4 -piperidy1]-3-(4 -phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine (36a) (0.800 g, yield: 59%).
LCMS m/z = 527.3 [M+1]+.
Date Recue/Date Received 2021-09-09 Step 2:
44444-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-l-y1]-1-piperidyl]cyclohexationc (36b) -CYO
N, N
\ H2N N
141-(1,4-dioxaspiro [4 . 5] decan-8-y1)-4-piperidy1]-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine (36a) (0.800 g, 1.52 mmol) was dissolved in 10 mL of tetrahydrofuran, and 10 mL of 4 N hydrochloric acid aqueous solution was added, the mixture was stirred at room temperature for 1 h. The reaction solution was concentrated, and to the residue was added 20 mL of dichloromethane.
The p1-I was adjusted to 9-10 with saturated sodium bicarbonate solution. The aqueous phase was further extracted with 20 mL of dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The resulting product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 19 : 1-9 : 1), to obtain 44444-amino-3 -( 4-phenoxyphenyl)pyrazolo [3 ,4 -djpyrimidin-1 -y1]-1 -piperidyl]cyclohexanone (36b) (0.600 g, yield: 82%).
LCMS m/z = 483.3 [M+1]+.
Step 3:
5-[144- [444-amino-3-(4-phenoxyphenyl)pyrazolo [3,4- dipyrimid in- I -yl] -1-piperidyl]cyclohcxyl]azetidin-3-yl]oxy-2-(2,6-dioxo-3-piperidyl)isoindolinc-1,3-dione (compound 36-a) 5-[1- [4- [444-amino-3-(4-phenoxyphenyl)pyrazolo [3,4-dipyri mid in -1-y11-1-piperidyl]cyclohexyl]azetidin-3-y floxy-2-(2,6-dioxo-3-piperidyl)isoindo linc-1,3-dione trifluoro acetate (compound 36-b) Date Recue/Date Received 2021-09-09 Q Q
-N Nl)---1-3 (cis) N

=

H2N\ N H2N \ N 0 N=i 5-(azetid in-3-y loxy)-2-(2,6-di oxo-3-piperidy 1)iso indo 1 ine-1,3-dione hydrochloride (34e) (0.056 g, 0.15 mmol) was dissolved in 2 inL of anhydrous methanol, and sodium bicarbonate solid (0.017 g, 0.20 mmol) was added. The mixture was stirred at room temperature for 20 minutes, and filtered, the filter cake was washed with I mL of methanol, and the filtrate was combined and concentrated, then the residue was dissolved in 2 mL of chloroform. 0.5 mL of DMSO, glacial acetic acid (0.018 0.30 mmol) and 4-[4 - [4-am ino -3 -(4-phenoxyphenyl)pyrazolo [3 ,4-d ]pyrimid in-l-y1]-1-piperidylicyclohexanone (36b) (0.11 g, 0.23 mmol) were successively added. Upon completion of the addition, the reaction was stirred at 70 C for 5 h, and cooled to room temperature. Sodium triacetoxyborohydride (0.064 g, 0.30 mmol) was added, and the reaction was carried out at room temperature overnight. To the reaction system was added dropwise saturated sodium bicarbonate solution to adjust the pH to 9-10, and 20 rnL of dichloromethane was added. The liquid separation was conducted, the aqueous layer was further extracted with 10 mL of dichloromethane once, and the organic layers were combined, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (diehloromethane/methanol (v/v) = 100: 0-6 : 1), to obtain the pure product 5 -[1444444-anai no-3 -(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin- I -y1.1- I -piperidylicyclohexyl jazetidin-3-y1 joxy-2-(2,6-dioxo-piperidyl)isoindoline-1,3-dione (compound 36-a) (0.020 g) and another isomer crude product. The crude product was passed through Pre-HPLC (instrument and preparative column: using Glison (IX-281 to prepare the liquid phase, preparative column model: Sunfire C18, 5 urn, inner diameter x length = 30 mmx 150 mm).
Preparation method: The crude product was dissolved with methanol and dimethyl sulphoxide, and filtered with 0.45 um filter membrane, to prepare into a sample Date Recue/Date Received 2021-09-09 solution. Mobile phase system: acetonitrile/water (containing 0.1% TFA).
Gradient elution method: gradient elution with acetonitrile from concentration of 5% to concentration of 60% (elution time: 15 min), the reaction system was lyophilized to obtain the pure product 5-11 -1444-14-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-l-y11-1-piperidyl]cyclohexyliazeti din-3-yfloxy-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione trifluoroacetate (compound 36-b) (7 mg).
Compound 36-a: (developing solvent: dichloromethane/methanol = 10 : 1, Rf value = 0.45) 111 NMR (400 Mllz, DMSO-d6) 6 11.09 (s, III), 8.27 (s, 111), 7.89 - 7.83 (m, 1H), 7.66 (d, 2H), 7.47 - 7.41 (m, 211), 7.33 - 7.28 (m, 211), 7.23 - 7.10 (m, 5H), 5.16 - 5.00 (m, 3H), 187 - 3.75 (m, 21-1), 3.58 - 3.39 (m, 4H), 3.22 - 3.05 (m, 3H), 2.95 -2.84 (m, 11-1), 2.68 - 2.53 (m, 311), 2.46 - 2.40 (in, 1H), 2.26 - 2.14 (m, 2H), 2.09 -1.95 (m, 211), 1.84- 1.68 (m, 5H), 1.49- 1.37 (m, 3H).
LCMS m/z = 796.3 [M+1]+.
Compound 36-b: (developing solvent: dichloromethane/methanol = 10: 1, Rf value ¨ 0.35) 'H NMR (400 MHz, DMSO-d6) 6 11.11 (s, 1H), 8.30 (s, 1H), 7.92 (d, 1H), 7.74 - 7.61 (m, 2H), 7.50- 7.32 (m, 411), 7.26 -7.09 (in, 5H), 5.38 -5.29 (in, 114), 5.18 -5.05 (m, 2H), 4.78 - 4.63 (m, 2H), 4.43 - 4.24 (in, 2H), 3.66 - 3.56 (m, 2H), 3.28 -3.21 (m, 3H), 2.95 - 2.84 (m, 111), 2.68 -2.54 (in, 2H), 2.29 - 1.94 (m, 8H), 1.60 -1.45 (m, 2H), 1.36 - 1.22 (in, 4H).
LCMS in/z = 796.2 [M+1]'.
Example 37 54443- [444-amino-3-(4-phenoxyphenyl)pyrazolo [3,4-d]pyrimid in-1-y1]-1 -piperidyl]azetidin-l-ylicyclohexoxyl-2-(2,6-dioxo-3-piperidypisoindoline-1,3-dione (compound 37) p / _________________________________ ,(1.4 0 0.%"----N 0 N.-=-/
'--t1-1 Date Recue/Date Received 2021-09-09 0 Ny0 N
¨0 Step CE) Step 2 Slep r_o_>a 37a 37b 37c 37ci 0 IC/.0 0 1110 Step 4 0 /
Slep N

37e N=/ CompNH
ound 37 Step 1:
1,4-dioxaspiro[4.5]decan-8-ol (37b) r-OH
1,4-dioxaspiro[4.5]decan-8-one (37a) (LOU g, 6.40 mmol) was dissolved in 10 mL of anhydrous methanol, and sodium borohydride (0.484 g, 12.8 mmol) was slowly added. Upon completion of the addition, the reaction was carried out at room temperature for 20 minutes. To the reaction system was slowly added dropwise mL of saturated ammonium chloride aqueous solution, and the resulted solution was extracted with dichloromethane (30 mL x 2). The organic layers were combined, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain 1,4-dioxaspiro[4.51deean-8-ol (37b) (0.800 g, yield: 79%).
Step 2:
1,4-dioxaspiro[4.5]decan-8-y1 methanesulfonate (37c) 1,4-dioxaspiro[4.5]decan-8-ol (37b) (0.800 g, 5.06 mmol) was dissolved in 10 mL of dichloromethane, and triethylamine (1.28 g, 12.6 mmol) was added, and the mixture was cooled to 0 C in an ice bath, and then methanesulfonyl chloride (1.16 g, 10.1 mmol) was slowly added. Upon completion of the addition, the mixture was slowly warmed to room temperature and reacted for 2 h. To the reaction system was added 20 mL of saturated sodium bicarbonate solution and 20 mL of diehloromethanc.
The liquid separation was conducted, and the organic layer was dried over anhydrous Date Recue/Date Received 2021-09-09 sodium sulphate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ¨ 1 : 4-3 : 7), to obtain 1,4-dioxaspiro[4.5jdecan-8-y1 methanesulfonate (37e) (0.640 g, yield: 54%).
Step 3:
5-( I ,4-d ioxaspi ro [4.51decan-8-yloxy )-2-(2,6-dioxo-3-pi peridyl)i soindol Me-1,3-dione (37d) 2-(2,6-dioxopiperidin-3-y1)-5-hydroxyl isoindoline-1,3-dione (34c) (see US20180099940 for the synthetic method) (0.0500 g, 0.182 mmol) was dissolved in 2 mL of DMF, and 1,4-dioxaspiro[4.5]decan-8-y1 methanesulfonate (37c) (0.0474 g, 0.201 mmol) and cesium carbonate (0.119 g, 0.365 mmol) were added. Upon completion of the addition, the reaction was stirred at 110 C under microwave for 2 h. The reaction solution was cooled to room n temperature, and 20 ITIL of water and 50 is mL of ethyl acetate were added. The liquid separation was conducted, the aqueous layer was further extracted with 20 mL of ethyl acetate, and the organic layers were combined. The organic phase was washed with 20 mL of saturated sodium chloride, dried over anhydrous sodium sulphate, and concentrated under reduced pressure.
The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) = 1 : 4-1 : 1), to obtain 5-(1,4-clioxaspiro[4.5]decan-8-yloxy)-2-(2,6-dioxo-3-piperidypisoindoline-1,3-dione (37d) (0.0240 g, yield:
32%).
LCMS m/z = 415.1 [M+1] .
Step 4:
2-(2,6-dioxo-3-piperidy1)-5-(4-oxocyclohexoxy)isoindoline-1,3-dione (37e) Date Recue/Date Received 2021-09-09 5-(1,4-dioxaspiro [4.5] decan-8-yloxy)-2-(2,6-dioxo-3-piperidyl)isoindol ine-1,3-dione (37d) (0.024 g, 0.058 mmol) was dissolved in 5 mL of tetrahydrofuran, and mL of 4 N hydrochloric acid aqueous solution was added, the mixture was stirred at room temperature for I h. The reaction solution was concentrated, and to the crude 5 product was added 20 mL of dichloromethane. The pH was adjusted to 9-10 with saturated sodium bicarbonate solution. The liquid separation was conducted, the aqueous layer was further extracted with 20 mL of dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain 2-(2,6-dioxo-3-piperidy1)-5-(4-oxocyclohexoxy)isoindoline-1,3-dione (37e) (0.021 g, yield: > 99%).
LCMS m/z 371.1 [M+1]' Step 5:
54443- [444-amino-3-(4-phenoxyphenyppyrazolo[3,4-dipyrimidin-1-y11-1-piperidyljazetidin-l-ylicyclohexoxy]-2-(2,6-dioxo-3-piperidypisoindoline-1,3-dione (compound 37) N

N" çNH
1 41-(azetid in-3-y1)-4- piperidy11-3-(4-phenoxyphenyl)pyrazolo [3,4-d]pyrimidin-4-amine (17b) (0.025 g, 0.057 inmol) was dissolved in 2 mL of chlorofoini, and glacial acetic acid (0.0068 g, 0.11 mmol) and 2-(2,6-dioxo-3-piperidy1)-5-(4-oxocyclohexoxy)isoindolinc-1,3-dione (37e) (0.021 g, 0.057 mmol) were added. Upon completion of the addition, the reaction was stirred at 70 C
for 5 h, and cooled to room temperature. Sodium triacetoxyborohydride (0.024 g, 0.11 mmol) was added, and the reaction was carried Out at room temperature overnight.
To the reaction solution was added dropwise saturated sodium bicarbonate solution to adjust the pH to 9-10, and 20 mL of dichloromethane was added. The liquid separation was conducted, the aqueous phase was further extracted with 10 mL
of Date Recue/Date Received 2021-09-09 dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 100 : 0-6: 1), to obtain 544434444-amino-3-(4-phen oxyphenyl)pyrazolo [3 ,4-d] pyri mi din-1 -y1]-1-p iperi dyl] azeti din-1 yl] cyc loltexoxy] -2-(2,6-di oxo-3 -piperi dy soindol ine-1,3 -dione (compound 37) (0.020 g, yield: 44%).
'1-1NMR (400 MHz, DMSO-d6) 8 11.09 (s, 1H), 8.26 - 8.20 (m, 11-1), 7.86 - 7.77 (m, 111), 7.69 - 7.63 (m, 211), 7.50- 7.39 (m, 311), 7.38 - 7.32 (m, 111), 7.23 - 7.08 (m, 5H), 5.15 - 5.07 (m, 111), 4.81 - 4.59 (m, 211), 3.60- 3.39 (m, 3H), 2.95 -2.81 (m, 4H), 2.64- 2.53 (m, 2H), 2.26 -2.11 (m, 3H), 2.10- 1.73 (m, 9H), 1.70- 1.36 (m, 5H).
LCMS m/z = 796.3 [M 1]+.
Example 38 5-[3-[3- [(3 S,4R)-4-[4-amino-3-(4-phenoxyphenyl)pyrazol o[3 ,4-d]pyrim id in-yl] -3-fluoro- 1-piperidyl]azetidin-1-y1]azetidin-1-y1]-2-(2,6-dioxo-3-piperidyl )isoindol me-1,3-dione (compound 38) oN

Date Recue/Date Received 2021-09-09 H..N N_,-.õ\
0 1 ,., I-12N --___:(\
Ft:J.-rU...ØK, si,i, i F=..-"--N.-jj-.0,2(..., Step 2 0 -F
\r4..1,4 (s) SILT 3 0 . ,,N, (R) Ha' Ms0' ------ N .0 (\-:4j N't) NH
-6 ....õ , 38a 38b 38c (1.),,,.., n' 38d N---...\
Sum4 F Step 5 (a) Sul, 6 ----------- IP.

o \---4,Boc C5 VNH
38e 38f H2N \ .'N
HaN
l F ' F Step S

..,a NH
38g N-Boc 38h F
\N-N,--s,., 6(R) t -.-N

Compound 38 ou N 0 ¨AC

Step 1:
tert-butyl (3S,4S)-3-fluoro-4-methylsulfonyloxy-piperidine-1-carboxylate (38b) f..!..).) mscr Tert-butyl (3S,4S)-3-fluoro-4-hydroxypiperidine- 1 -carboxylate (38a) (2.0 g, 9.13 mmol) was dissolved in 30 triL of dichloromethane, and DIPEA (4.48 g, 34.66 mmol) was added, then methanesulfonyl chloride (1.6 g, 13.97 mmol) was slowly added dropwise. Upon completion of the addition, the mixture was stirred at room temperature for 2 h. The reaction solution was quenched with 40 mL of water, and extracted with 100 mL of DCM three times. The organic phase was washed with iriL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 5 : 1), to obtain tert-butyl Date Recue/Date Received 2021-09-09 (3S,4S)-3-fluoro-4-methylsulfonyloxy-piperidine-1-carboxylate (38b) (2.65 g, yield:
98%).
Step 2:
tert-butyl (3S,41()-444-amino-3-(4-phenoxyphenyl)pyrazolo13,4-d[pyrimidin-s 1-yI]-3-fl uoro-pi peridine-l-carboxylate (38c) N
0 `N
(R) = NL
Tert-butyl (3S,4S )-3 -11uoro-4 -methylsul fonyloxy-piperidine-1 -carboxyl ate (38b) (2.45 g, 8.25 mmol) and 3-(4-phenoxypheny1)-11-1-pyrazolo[3,4-djpyrimidin-4-amine (1.0 g, 3.30 mmol) were dissolved in 20 mL of DMF, and cesium carbonate (2.14 g, 6.6 mmol) was added, the reaction was stirred at 100 C for 7 h. The reaction was cooled to room temperature, and the reaction system was added 50 mL of water, and extracted with 100 mL of ethyl acetate three times. The organic phase was washed with 100 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethanc/methanol (v/v) = 15 : 1), to obtain tert-butyl (3S,4R)-4-14-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-dipyrimidin-1-y1]-3-fluoro-piperidine-l-carboxylate (38c) (0.9 g, yield: 54%).

LCMS rn/z = 505.3 [M+ 1]'.
Step 3:
1 -[(3 S ,4R)-3 -fluoro-4-piperidyl] -3 -(4-phenoxyphenyl)pyrazo lo [3,4-d]pyrimidin-4-amine (38d) N
0 =
(R) 4111. NH
Tert-butyl (3S,4R)-444-amino-3-(4-phenoxyphcnyl)pyrazolo[3,4-d]pyrimidin-Date Recue/Date Received 2021-09-09 1-y1]-3-fluoro-piperidine-1-carboxylate (38c) (0.9 g, 1.79 mmol) was dissolved in 10 mL of DCM, and 5 mL of trifluoroaeetic acid was added, the mixture was stirred at room temperature for 4 h. The reaction system was directly concentrated under reduced pressure, and the residue was dissolved with 60 mL of 5 N sodium hydroxide solution, extracted with 100 mL of dichloromethane three times, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, to obtain [(3S,4R)-3 -fluoro-4-piperidy1]-3 -(4-phenoxyphenyl)pyrazo1o[3 ,4-djpyrimidin-amine (38d) (0.7 g, yield: 97%).
LCMS m/z = 405.2 [M 1].
Step 4:
tert-butyl 3-[(3 S,4R)-444-amino-34 4-phenoxyphenyl)pyrazo lo [3 ,4-d]pyrirn idin-1 -y1]-3-fluoro-1-piperidy liazetidine-1 -carboxylate (38e) H2N \ N
F
0 (R) Boc 1-[(3S,4R)-3-fluoro-4-piperidy1]-3-(4-phenoxyphenyl)pyrazolo[3,4-3.5 djpyrimidin-4-amine (38d) (0.7 g, 1.73 mmol) was dissolved in 35MI of DCE and 5 mL of DMSO, and tert-butyl 3-oxoazetidine- 1 -carboxylate (542 mg, 3.17 mmol) were added, the mixture was stirred at room temperature for 10 minutes, then sodium triacetoxyborohydride (1.68 g, 7.93 mmol) was added, and the mixture was stirred at room temperature overnight. To the reaction solution was slowly added 30 mL of saturated sodium bicarbonate solution, and the mixed solution was extracted with 50 mL of ethyl acetate three times. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20 : 1), to obtain tert-butyl 3-[(3S,4R)-444-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-l-y1]-3-fluoro-1-piperidyljazetidinc- 1 -carboxylate (38e) (0.88 g, yield: 91%).
LCMS m/z = 560.5 [M 1]4 .
Date Recue/Date Received 2021-09-09 Step 5:
1-43 S,4R)-1-(azetidin-3-y1)-3-fluoropiperidin-4-y1)-3 -(4-phenoxypheny1)- 1 1-pyrazolo [3 ,4-d]pyrimidin-4-amine (381) H2N \ /N F
N N (s) NH
0 \ (R) Tert-butyl 3 -[(3 S
,4R)-444-amino- 3 -(4-phenoxyphenyl)pyrazolo [3 ,4-d]pyrimidin- 1-y11-3 -fluoro- 1 -pip eridy Ilazetidi ne- 1 -carboxylate (3 8e) (880 mg, 1.57 mmol) was dissolved in 20 iriL of DCM, and 5 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 h. Upon completion of the reaction, the system was directly concentrated under reduced pressure, and the residue was dissolved with 50 mL of 5 N sodium hydroxide solution, and extracted with 50 mL
of DCM three times. The organic phase was washed with 30 mL of 1 N sodium hydroxide solution twice, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, to obtain 1-((3S,4R)-1-(azetidin-3-y1)-3-fluoropiperidin-4-y1)-3-(4-phenoxypheny1)-1H-pyrazole[3,4-d]pyrimidin-4-amine (381) (0.65 g, is 90%).
LCMS m/z = 460.3 [M+1]t Step 6:
tert-buty I 3 43 -R3 S,4R)-444-am ino-3 -(4 -phenoxyphenyl)pyrazolo[3 õ4-d]pyrimidin- I -y1]-3 -fluoro- 1 -piperidyl 1 azetidi n-1 -ylj azetidine- 1 -carboxylate (38g) H2N \ N
0 (13) _Boc 1 -((3 S,4R)-1 -(azetidin-3-y1)-3 -11uoropiperidin-4-y1)-3 -(4-phenoxypheny1)-pyrazole[3 ,4-d]pyrimidin-4-amine (381) (650 mg, 1.42 mmol) was dissolved in mL of DCE and 2 mL of DMSO, and tert-butyl 3-oxoazetidine-1 -carboxylate (485 Date Recue/Date Received 2021-09-09 mg, 2.84 mmol) was added, the mixture was stirred at room temperature for 10 minutes, then sodium triacetoxyborohydride (1.12 g, 5.28 mmol) was added, and the mixture was stirred at room temperature overnight. To the reaction system was slowly added 60 mL of saturated sodium bicarbonate solution, and the mixed solution was extracted with 60 mL of ethyl acetate three times. The organic phase was washed with 50 niL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20 : 1), to obtain tert-butyl 3-[3-[(3S,4R)-4-[4-amino-3-(4-phenoxypheny1)]pyrazolo [3,4-d]pyrimid in-1 0 y1]-3-fluoro- 1-p iperidyl]azetidin -1-yl]azetidin e-l-carboxylate (38g) (0.46 g, 53%).
LCMS m/z = 615.6 [M+1].
Step 7:
1-[(3S,4R)-1 41-(azetid in-3-yl)a zetid in-3-y1]-3-flu oro-4-piperidy1]-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine (38h) ' F
=
0 Nip N (R) Tert-butyl 3-[3-[(3 S,4R )-444-am ino-3-(4-phenoxyphenyl)lpyrazolo [3,4-d]pyrim idin-l-y11-3-fluoro-l-piperidyliazetidin-l-yllazetidine-1-carboxylate (38g) (400 mg, 0.65 mmol) was dissolved in 20 mL of DCM, and 4 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 h. The reaction system was directly concentrated under reduced pressure, and the residue was dissolved with 30 mL of 5 N sodium hydroxide solution, and extracted with 30 mL
of DCM three times. The organic phase was washed with 30 inL of 1 N sodium hydroxide solution twice, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, to obtain 1-[(3SAR)-141-(azetidin-3-yl)azetidin-3-y1]-fluoro-4-piperidy1]-3-(4-phenoxyphenyl)pyrazolo [3 ,4-d]pyrimidin-4-amine (38h) (0.28 g, yield: 84%).
Date Recue/Date Received 2021-09-09 LCMS m/z = 515.5 [M+1].
Step 8:
54343- [(3S,4R)-444-amino-344-phenoxypheny Opyrazol o[3 ,4-d]pyrimid in-1-y11-3 -fluoro-l-piperidyl jazetidin- 1 -y1 jazeticli n-l-y11-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (compound 38) N
KR, co 1- [(3 S,4R)-1-[1-(azetid in-3 -yl)azetid in-3 -y1]-3-fluoro-4-piperidy1]-3-(4-phenoxyphenyl)pyrazolo[3,4-djpyrimidin-4-amine (38h) (0.28 g, 0.54 mmol) was dissolved in 25 mL of DMSO, and 3 mL of DIPEA and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (300 mg, 1.09 mmol) were added, the reaction was stirred in an external bath at 80 C for 5 h. The reaction solution was cooled to room temperature, added 50 mL of water, and extracted with 100 mL of ethyl acetate. The organic phase was washed with mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced is pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethanc/methanol (v/v) = 20 : 1), to obtain 5-[3-[3-[(3S,4R)-4-[4-amino-3-(4-phenoxyphenyl)pyrazolo [3,4-d]pyrimidin- I -y11-3 -fluoro-1 -p iperidyllazetidin- 1-yl]azetidin- 1-y1]-2-(2,6-d ioxo-3-piperidyl)isoindoline-1,3-dione (compound 38) (0.126 g, yield: 30%).
111 NMR (400 MHz, CDC13) 6 8.91 (s, 111), 8.38 (s, 1H), 7.69 - 7.61 (m, 311), 7.43 -7.35 (m, 2H), 7.21 -7.05 (m, 5H), 6.79 (d, 1H), 6.53 (dd, 1H), 5.68 (brs, 211), 5.20 - 5.01 (m, 1H), 4.99 - 4.82 (m, 2H), 4.10 - 4.02 (m, 2I1), 3.96 - 3.87 (m, 2H), 3.80 - 3.66 (m, 1H), 3.66 - 3.56 (m, 2H), 3.32 -2.97 (m, 6H), 2.92 - 2.65 (m, 3H), 2.49 - 2.29 (m, 114), 2.29 - 2.19 (m, 111), 2.17 -2.07 (m, 214).
LCMS m/z = 771.3 [M+1r.
Example 39:
Date Recue/Date Received 2021-09-09 5-(3-((3R,4R)-4-(4-amino-3-(4-phenoxypheny1)-111-pyrazo10[3,4-d]pyrimidin-I -y1)-3-fluoropiperidin-1-y1)41,3'-biazetidini-P-y1)-2-(2,6-dioxopiperidin-3-ypisoindoline-1,3-dione (compound 39) N"----=N F., H2N \ 411 N--(R \) N¨CN¨CN 0 /
N,....õ---..õ

H
N.:_-, 1.-12N r '6-'1 I-42N
\ 7N
F \ 7N
%rt) 7(R) SILT 1 F(t.t) swp 4 140,C.,i- Step 1 M513,=6;'," SwF, 2 - (R) - y 0 __________ Boc Boc ....,N b N' N,Boo 6 39c1 39b 3,9c N.---,, 1-12N
Id2N \ ON
/ F - (R) Ye', ( ,,i.õ1,,,,'---, 7 SR) SteP ) _N._ 0 1,1 N 1 = - - e ¨ ' - -( = \ I N ki 0 N ,,), AL.,,,..-\
-6 - \---NH o Boc =
39f 39g ase u2N
\ 7N
H2N1_,. .1;
\ z N
\ 1 .(1?) F
''-, (R) Slep 8 \ / N-N.C1 Sip 7 e .\,, cN SR) ________ y 0 IN *Ã-1, N,,.1 \--NH \---N, `.... 0 0 NH

39h Compound 39 I N

õ...
'6 Step 1:
tert-butyl (3R,4S)-3-fluoro-4-((methylsulfonyl)oxy)piperidine-I-carboxylate (39b) F
Ms0,, õ...---...,,:(R) -...õ.õ...N_ Boc Ted-butyl (3R,4S)-3-fluoro-4-hydroxypiperidine-1 -carboxylate (39a) (2.0 g, 9.13 mmol) was dissolved in 30 mL of dichloromethane, and DIPEA (2.76 g, 21.35 Hilltop was added. The mixture was cooled to 0 C, and methanesulfonyl chloride (1.25 g, 10.91 mmol) was slowly added dropwise. Upon completion of the addition, is the mixture was stirred at room temperature for 30 minutes. Upon completion of the Date Recue/Date Received 2021-09-09 reaction, the reaction was quenched by adding 40 mL of water, and extracted with 50 mL of dichloromethane. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3 : 1), to obtain tert-butyl (3R,4S)-3-fluoro-4-((methylsulfonyl)oxy)piperidine- 1 -carboxylate (39b) (2.7 g, yield: > 99%).
Step 2:
tert-butyl (3R,4R)-4-(4-amino-3 -(4-phenoxypheny1)-1H-pyrazolo [3,4-d]pyrim idin-l-y1)-3 -fluoropiperidine-l-carboxylate (39c) N
0 \
(R) 110.
Tert-butyl (3 R,4S)-3 -fluoro-4-((methyl sulfonyl)oxy)piperi dine-l-earboxyl ate (39b) (2.20 g, 7.41 mmol) and 3-(4-phenoxypheny1)-1H-pyrazolo[3,4-djpyrimidin-4-amine (1.0g. 3.30 annul) were dissolved in 30 mL of DMF, and cesium carbonate (3.23g. 9.91 mmol) was added, the reaction was stirred at 100 C for 4 h. The reaction is solution was cooled to room temperature, to same was added 50 rriL of water, and extracted with 50 mL of ethyl acetate. The organic phase was washed with 50 mL
of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 50 : 1), to obtain tert-butyl (3R,4R)-4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-1-y1)-3-fluoropiperidine- 1 -carboxylate (39e) (900 mg, yield: 54%).
LCMS m/z = 505.3 [M+1]+.
Step 3:
I R,4R )-3 fluoropiperidin-4-yI)-3-(4-pbenox ypheny1)-1H -pyrazol o[3,4-d]pyrimidin-4-amine (39d) Date Recue/Date Received 2021-09-09 /N
0 \N-N 7 (R) NH
Tert-buty I (3 R,4R)-4-(4-ami no-3 -(4-phenoxypheny1)-1H-pyrazo lo [3,4-d]pyrimidin-l-y1)-3-fluoropiperidine-1-carboxylate (39c) (900 mg, 1,79 mmol) was dissolved in 15 mL of dichloromethane, and 10 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 h. The reaction system was directly concentrated under reduced pressure, and the residue was dissolved with 30 mL
of 5 N sodium hydroxide solution, extracted with 50 mL of dichloromethane, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, to obtain ((3R,4R)-3-fluoropiperidin-4-y1)-3 -(4-phenoxypheny1)-1H-pyrazolo [3 ,4-io (39d) (670 mg, yield: 93%).
LCMS m/z = 405.3 [M+1] .
Step 4:
tert-butyl 3 -((3 R,4R)-4-(4-amino-3-(4-phenoxypheity1)-1H-pyrazolo [3,4-d]pyrimidin-l-y1)-3-fluoropiperidin-l-ypazeti dine-1-carboxyl ate (39e) Nz-F
N
0 r N (R) ""Boc 1-((3R,4R)-3-fluoropiperidin-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (39d) (670 mg, 1.66 mmol) was dissolved in 35 mL of DCE, and tert-butyl 3-oxoazetidine- 1 -carboxylate (566 mg, 3.31 mmol) was added, the mixture was stirred at room temperature for 10 minutes, then sodium triacetoxyborohydride (1.4 g, 6.61 mmol) was added, and the mixture was stirred at room temperature overnight. To the reaction solution was slowly added 30 mL of saturated sodium bicarbonate solution, and the mixed solution was extracted with 30 mL of dichloromethane three times. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced Date Recue/Date Received 2021-09-09 pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20 : 1), to obtain tert-butyl ((3R,4R)-4-(4-amino-3-(4 -plienoxypheny1)-1H-pyrazo lo[3 ,4-djpyrimidin- I -y1)-3-fluoropiperidin-l-y0azetidine-1-carboxylate (39e) (860 mg, yield: 93%).
LCMS in/z = 560.3 [M I]'.
Step 5:
I -((3R,4R)-14azetidin-3-y1)-3-fluoropiperidin-4-y1)-3-(4-phenoxypheny1)- I H-pyrazolo [3 ,4-djpyrimi din-4-amine (390 N-Th E
(R) Tert-butyl 3-((3R,4R)-4-(4-anaino-3- (4-phenoxypheny0-1H-pyrazolo [3 ,4-d]pyrimidin- 1-y1)-3-f1uoropiperidin-1 -yl)azcti dinc-l-carboxylate (39c) (810 mg, 1.45 mmol) was dissolved in 20 mL of DCM, and 5 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 h. Upon completion of the reaction, the system was directly concentrated under reduced pressure, and the residue was dissolved with 30 mL of 5 N sodium hydroxide aqueous solution, and extracted with 30 mI, of DCM three times. The organic phase was washed with 30 mL of 1 N sodium hydroxide solution twice, dried over anhydrous sodium sulphate, and concentrated to obtain 1 -((3R,4R)-1-(azeti din-3 -y1)-3-fluompiperidi n-4-y1)-3 -(4-phenoxypheny0-1H-pyrazolo[3,4-d]pyrimidin-4-amine (390 (0.63 g, yield: 95%).
LCMS m/z = 460.2 [M+1]F.
Step 6:
tert-butyl 3-((3R,4R)-4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrim idi n-1 -y1)-3-fluoropiperidin-1-y1)41,3'-bi azeti dine] -1'-carboxylate (39g) N
0 N Or() o 1-((3R,4R)-1-(azetidi n-3 -y1)-3-fluoropiperidin-4 -y1)-3-(4 -phcn oxyphcnyI)-Date Recue/Date Received 2021-09-09 pyrazolo[3,4-d]pyrimidin-4-amine (390 (580 mg, 1.26 mmol) was dissolved in 30 mL of DCE, and tert-butyl 3-oxoazetidine- 1 -carboxylate (432 mg, 2.53 mmol) was added, the mixture was stirred at room temperature for 10 minutes, then sodium triacetoxyborohydride (1.07 g, 5.05 mmol) was added, and the mixture was stirred at room temperature overnight. To the reaction system was slowly added 30 mL of saturated sodium bicarbonate solution, and the mixed solution was extracted with 30 mL of dichloromethane three times. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20 : 1), to obtain tert-butyl ((3R,4R)-4-(4-amino-3-(4-phenoxypheny1)- 114-pyrazolo[3,4-d]pyrimidin-l-y1)-3-fluoropiperidin-l-y1)41,3t-biazetidine]-1'-carboxylate (39g) (600 mg, yield:
77%).
LCMS m/z = 615.3 [M l. 7:
14(3 R,4R)-1-([1,3'-biazetidin]-3 -y1)-3-fluoropiperidin-4-y1)-3-(4-phenoxypheny1)- I H-pyrazo lo[3 ,4-cl]pyrim id in-4-am ine (39h) F
(R) 0 \ NN (R) o\--NH
Tert-butyl 3-((3R,4R)-4-(4-am ino-3 -(4-plienoxy plieny1)-1 H-py razolo [3 ,4-(1] pyrim idin- 1-y1)-3 -fluoropiperi din-1-y1)-[1,31- bi azeti dine] - I '-carboxylate (39g) (550 mg, 0.896 mmol) was dissolved in 20 mL of DCM, and 4 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 h. The reaction system was directly concentrated under reduced pressure, and the residue was dissolved with 30 mL of 5 N sodium hydroxide solution, and extracted with 30 mL
of DCM three times. The organic phase was washed with 30 mL of 1 N sodium hydroxide solution twice, dried over anhydrous sodium sulphate, and concentrated to obtain 1-((3R,4R)-1-([1,3t-biazetidin]-3-y1)-3-fluoropiperidin-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (39h) (0.43 g, yield: 93%).

LCMS m/z = 515.2 [M--1r.
Date Recue/Date Received 2021-09-09 Step 8:
-(3 -((3RAR)-4-(4-amino-3 -(4-phenoxypheny1)-114-pyrazolo [3 ,4-d]pyrimidin-1-y1)-3-11 uoropiperidin-l-y1)-[1,3'-biazeti dinj-1i-y1)-2-(2,6-dioxopiperidin-yl)isoi ndoline-1,3-dione (compound 39) E
H2N- 1 (R) No-ki N¨CN¨CN
el 0 0¨N-0 14(3 R,4R)-1-([1,31-biazeti din]-3 -y1)-3-flu oropi peri din-4-yI)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (39h) (300 mg, 0.584 mmol) was dissolved in 25 mL of DMSO, and 1.5 mL of DIPEA and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (274 mg, 0.993 mmol) were added, the reaction was stirred in an external bath at 80 C for 5 h. The reaction solution was cooled to room temperature, added 50 mL of water, and extracted with 100 mL of ethyl acetate. The organic phase was washed with 100 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (diehloromethane/methanol (v/v) = 15 : 1), to obtain 5-(3-((3R,4R)-4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazo lo[3 ,4-d]pyrimidi n- 1-y1)-fluoropiperidin-l-y1)41,3'-biazeti din]-1'-y1)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (compound 39) (300 mg, yield: 67%).
1H NMR (400 MHz, CDC13) 6 9.61 (s, 1H), 8.41 (s, 1H), 7.69 - 7.61 (m, 3H), 7.43 - 7.35 (m, 211), 7.20 - 7.05 (in, 511), 6.79 (d, III), 6.53 (dd, 111), 5.80 (brs, 211), 5.35 - 5.14 (in, 1H), 4.97 - 4.83 (m, 2H), 4.09 - 4.01 (in, 2H), 3.93 - 3.85 (in, 2H), 3.75 - 3_55 (m, 3H), 3.29 - 3_05 (m, 41-1), 2_92 - 2.64 (m, 4H), 2.53 - 2.39 (m, 1H), 2.22 - 2.05 (m, 411).
LCMS m/z = 771.3 [M+1]' Example 40:
5-(3 -((3R,4R)-4-(4-amino-3-(4 -phenoxypheny1)-1H-pyrazolo [3 ,4-d]pyrimidin-1-yI)-3-fluoro-[1,4'-bi piperi din] -1'-yl)azetidi n-l-y1)-2-(2,6-dioxopiperi din-3-Date Recue/Date Received 2021-09-09 yflisoindoline-1,3-dione (compound 40) N=2:\

H2N< \ /< N F., (R) --- t 0z- (R)-1 0 H
,, ¨C\ 0N--ON N

II, \
H2N 5 H2N ,1q--- H2N
\ õ N \ / N
F E Step 2 F Step 3 Step 1 \ _ NI 7 (13} __ P.-'The--1 O \ N = { ' __ 0 0 N

NH
a N 11-D
N
(15 39d 40a N,Boc 406 H2N B2N .., N
P P
a \ --N -;sR) Step 4 N tIN ¨N.-1.1---\
\--NH
N'Boc 400 40d H2N N_-,,\
'I /N ...
- (7 Compound 40 --- ---.\

Step 1:
tert-butyl (3R,4R)-4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-1-y1)-3-fluor041,4'-bipiperidine]-1'-earboxy1ate (40a) H2N N.,-___\
1 ,N
F
d-<___\ / \N-N.,.õ0-,37,1 --............N,----) -- N.
I -( (3R,4R)-3-fluoropiperidin-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (39d) (800 mg, 1.98 mmol) was dissolved in 35 mL of DCE, and tert-butyl 4-oxopiperidine-1-carboxylate (787 mg, 3.95 mmol) was added, the mixture was stirred at room temperature for 10 minutes, then sodium Date Recue/Date Received 2021-09-09 triacetoxyborohydride (1.68 g, 7.93 mmol) was added, and the mixture was stirred at room temperature overnight. To the reaction solution was slowly added 30 mL of saturated sodium bicarbonate solution, and the mixed solution was extracted with 30 mL of DCM three times. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20: 1), to obtain tert-butyl (3R,4R)-444-amino-3 -(4-phenoxypheny1)-1H-pyrazolo [3,4-d]pyrimidin-l-y1)-3 -fluoro- [1 bipiperidinej- 1?-carboxylate (40a) (970 mg, yield: 83%).
LCMS m/z = 588.3 [M+1] .
Step 2:
1-((3R,4R)-3-fluoro41,4'-bipiperidin]-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo13,4-dipyrimidin-4-amine (40b) N

(1115 CR) I
Tert-butyl (3R,4R)-4-(4-amino-3 -(4-phenoxypheny1)-111-pyrazolo [3,4-d]pyrimidin-l-y1)-3 -fluoro- [1,4'-bip iperidinel-lt-carboxylate (40a) (960 mg, 1.64 mmol) was dissolved in 20 mL of DCM, and 8 mL of trifluoroacefic acid was added, the mixture was stirred at room temperature for 4 h. Upon completion of the reaction, the system was directly concentrated under reduced pressure, and the residue was dissolved with 30 mL of 5 N sodium hydroxide solution, and extracted with 30 mL
of DCM three times. The organic phase was washed with 30 mL of 1 N sodium hydroxide solution twice, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain 14(3R,4R)-3-fluoro-[1,4'-bipiperidin]-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (40b) (0.79 g, yield: 99%).
LCMS m/z = 488.3 [M+1].
Step 3:
tert-butyl 3 -((3R,4R)-4-(4-amino-3 -(4-phenoxypheny1)-1H-pyrazolo [3,4-d]pyrimidin-l-y1)-3 -fluoro-[1,4'-bipiperidin] -1`-ypazetidine-1-carboxylate (40c) Date Recue/Date Received 2021-09-09 N
0 \N
(FZ
\¨N,Boo 1-43R,4R)-3-fluoro-[1,4'-bipiperidin]-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (40b) (540 mg, 1.11 mmol) was dissolved in 30 mL of DCE, and tert-butyl 3-oxoazetidine- 1 -carboxylate (380 mg, 2.22 mmol) was added, the mixture was stirred at room temperature for 10 minutes, then sodium triacetoxyborohydride (940 mg, 4.44 mmol) was added, and the mixture was stirred at room temperature overnight. To the reaction system was slowly added 30 triL
of saturated sodium bicarbonate solution, and the mixed solution was extracted with 30 mL of DCM three times. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20 : I), to obtain tert-butyl 34(3R,4R)-4-(4-am ino-3-(4-plienoxypheny1)-1H-pyrazolo[3,4-d] pyrim idin-l-y1)-3-fluoro-[1,4'-bipiperidinj-r-yl)azetidine-1-carboxylate (40c) (630 mg, yield: 88%).
is LCMS m/z = 643.4 [M+1] .
Step 4:
1-((3R,4R)-11-(azetidin-3-y1)-3-fluoro41,4'-bipiperidin j-4-yI)-3 -(4-phenoxypheny1)-1H -pyrazo lo [3 ,4-d] pyrimi din-4- amine (40d) H2N , 1 E

(R) I
\--NH
Tert-butyl 3 -((3 R,4R)-4-(4-am inc-3 -(4-phe noxypheny1)-1H-pyrazolo [3,4-dipyrimidin- 1-y1)-3 -tluoro-1.1,4'-bi piperidin1-11-yl)azetidine-1-carboxyl ate (40c) (600 mg, 0.93 mmol) was dissolved in 20 mL of DCM, and 8 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 h. The reaction Date Recue/Date Received 2021-09-09 system was directly concentrated under reduced pressure, and the residue was dissolved with 30 mL of 5 N sodium hydroxide solution, and extracted with 30 mL
of dichloromethane three times. The organic phase was washed with 30 itiL of 1 N
sodium hydroxide solution twice, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain 1-((3R,4R)- 1'-(azetidin-3-y1)-3-fluoro-[1,41-b ipiperi din] -4-y1)-3 -(4-phenoxypheny1)-1H-pyrazolo [3,4-d] pyrim id in-4-am ine (40d) (0.47 g, yield: 93%).
LCMS tn/z = 543.3 [M+1] .
Step 5:
5-(3-43R,4R)-4-(4-ami no-3-(4-phenoxyphen yI)- I H-pyrazo lo [3 ,4-d]pyri midi n-1-y1 )-3-fluoro-[1,4'-bi piperi din] -l'-y Dazetidin-l-y1)-2-(2,6-dioxopi peri din-3-yl)isoindoline-1,3-dione (compound 40) H2N \ /N F
OR) N

1-((3R,4R)-1'-(azetidin-3-y1)-3-fluoro-[1,4'-bipiperidin]-4-y1)-3-(4-is phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (40d) (350 mg, 0.65 mmol) was dissolved in 25 mL of DMSO, and 1.5 mL of D1PEA and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (267 mg, 0.97 mmol) were added, the reaction was stirred in an external bath at 80 C
for 5 h. The reaction solution was cooled to room temperature, added 50 mL of water, and extracted with 100 mL of ethyl acetate. The organic phase was washed with mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 15 : 1), to obtain 5-(34(3R,4R)-4-(4-amino-3 -(4-ph enoxypheny1)-1H-pyrazolo [3,4-d]pyrimidi n- 1-y1)-3-fluoro-[1,4-bipiperidin]-1'-yl)azetidin-1-y1)-2-(2,6-dioxopiperidin-3-y1)isoindoline-1,3-dione (compound 40) (380 mg, yield: 74%).
111 NMR (400 MHz, CDC13) 6 9.76 (s, 11-1), 8.41 (s, 1H), 7.69 - 7.61 (m, 311), Date Recue/Date Received 2021-09-09 7.42 - 7.34 (m, 2H), 7.20 - 7.11 (m, 311), 7.11 - 7.05 (m, 214), 6.79 (d, 114), 6.52 (dd, 114), 5.83 (brs, 2H), 5.29 - 5.10 (m, 111), 4.97 - 4.80 (m, 214), 4.12 - 4.06 (m, 211), 3.95 - 3.85 (in, 2H), 3.45 - 3.31 (in, 2H), 3.06 - 2.92 (in, 311), 2.91 - 2.68 (m, 3H), 2.56 - 2.35 (m, 4H), 2.16- 1.93 (m, 4H), 1.92- 1.82 (m, 2H), 1.74- 1.58 (m, 2H).
LCMS m/z = 799.3 [M-F-1]-1.
Example 41:
5-(3-((3R,45)-4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazo1o[3,4-d]pyrimidin-1-y1)-3-fluoropiperidin-1 -y1)-{ 1,3'-bi azeti din] -1'-y1)-2-(2,6-dioxopiperidin-3 -yi)isoindoline-1,3 -dione (compound 41) N-,,-\
H2N \ / N F
r--, -N-N-E--A 0 H
N--_,-----"\ _ \ /

N.,-_, i-ici.,-(R) M90 - (R) t,,,,) S1)3 0_ ,. / \N,N,, ' (F0 Slep4 Step I (..."Ci) SlcP2 0 C IV ----- '1,4, Nõ.1:s_. --------1.6 , ' eNH
N'Bw C5, Boc 'Doc 41a 41 b 41c 41d N.----\
, I-12N N,-,,,, H2N---____/(-N F
H`2N,N
,.,, Step 41 git . ,õ,,,ci7 N N (LI Step 5 N 4 ----4, r 0 N (s) 0 Nr ' = (6) -i.- ..õ..õ4,0 \ i N tki Nõ,.__-\
1 --N-Boc 6 \---N'Boc 44j 4 4G
41f 41e 412N N-.....\
\ / N
F
N...,-,, r 42N ' \ / N
E (s) , (R) Sep Step 7 4 ... , ci _,.... o _,... 4:4 \ / N-N .
a N._--, NH
41h (:!11)d 41 - --'\

Step 1:
tert-butyl (3R,4R)-3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-earboxylate (41b) Date Recue/Date Received 2021-09-09 MsO
-(R) Tat-butyl (3R,4R)-3-fluoro-4-hydroxypiperidinc-1-carboxylate (41a) (3.0 g, 13.70 mmol) was dissolved in 80 mL of dichloromethane, and triethylamine (4.15 g, 41.09 mmol) was added, the mixture was cooled to 0 C, then methanesulfonyl chloride (1.88 g, 16.41 mmol) was slowly added dropwise. Upon completion of the addition, the reaction was stirred at room temperature for 30 minutes. The reaction solution was quenched with 40 m1_ of water, and extracted with 100 ml, of DCM
three times. The organic phase was washed with 100 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3 : 1), to obtain tert-butyl (3R,4R)-3-fluoro-4-((methylsulfonyl)oxy)piperidine-l-carboxylate (41b) (4.1 g, yield: > 99%).
Step 2:
tert-butyl (3R,4S)-4 -(4-am ino-3-(4-phenoxypheny1)-1H-pyrazo lo [3,4-d]pyrim id in-1 -y1)-3-fluorop iperidine- I -carboxyl ate (41c) N
N
(s) I
.Jr'Boc Tert-butyl (3R ,4R )-3 -fl uoro-4-((m ethyl sul fon yl)oxy)piperi din e-1 -carboxyl ate (41b) (3.92 g, 13.20 mmol) and 3-(4-phenoxypheny1)-11-1-pyrazolo[3,4-d]pyrimidin-4-amine (2.0 g, 6.60 mmol) were dissolved in 50 mL of DMF, and cesium carbonate (6.45 g, 19.80 mmol) was added, the reaction was stirred at 100 C for 4 h. The reaction was cooled to room temperature, and the reaction system was added 80 mL
of water, and extracted with 100 mL of ethyl acetate three times. The organic phase was washed with 100 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethanemethanol (v/v) ¨ 50 : 1), to Date Recue/Date Received 2021-09-09 obtain tert-butyl (3R,4S)-4-(4-amino -3-(4-phenoxyph eny1)-1 H-pyrazolo [3 ,4-d]pyrimidin- 1-y1)-3-fluoropiperidine-1-carboxylate (41c) (2.5 g, yield: 75%).
LCMS in/z ¨ 505.3 [M-Fl Step 3:
1 -((3 R,4 S)-3-fl uoropiperidi n-4-y1)-3 -(4-phenoxypheny1)-1H -pyrazo lo [3 ,4-d]pyrimidin-4-amine (41d) NN
0 (R) fik Tert-butyl (3 R,4S)-4-(4-am ino-3 -(4-phen oxyphen y1)-1 H-pyrazolo[3 ,4-d]pyrimidin- I -y1)-3 -fluoropiperi dine-1-carboxyl ate (41e) (2.5 g, 4.96 mmol) was dissolved in 60 mL of DCM, and 20 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 h. The reaction system was directly concentrated under reduced pressure, and the residue was dissolved with 60 mL
of 5 N sodium hydroxide solution, extracted with 100 iriL of dichlorornethane, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, to obtain is ((3R,4S)-3-fluoropiperidin-4-y1)-3 -(4-phenoxypheny1)-1H-pyrazolo[3 ,4-d]pyrimidin-4 -amine (41d) (2.1 g, yield: >99%).
LCMS m/z = 405.3 [M+ I r.
Step 4:
tert-butyl 3 -((3 R,4S)-4 -(4-amino-3 -(4-phenoxyphenyI)-111-pyrazolo [3,4 -d]pyrimidin-1 -yI)-3 -fluoropiperidin-1 -yl) azeti dine-1 -carboxyl ate (41e) F
(R) (S) Boc 1 -((3R,4S)-3 -flu oropiperidin-4-y1)-3 -(4-phenoxypheny1)-111 -pyrazolo [3,4 -d]pyrimidin-4-amine (41d) (900 mg, 2.23 mmol) was dissolved in 35 mL of DCE, and tert-butyl 3-oxoazetidine- 1 -carboxylate (762 mg, 4.46 mmol) was added, the Date Recue/Date Received 2021-09-09 mixture was stirred at room temperature for 10 minutes, then sodium triaeetoxyborohydride (1.89 g, 8.92 mmol) was added, and the mixture was stirred at room temperature overnight. To the reaction solution was slowly added 50 mL of saturated sodium bicarbonate solution, and the mixed solution was extracted with 50 mL of DCM three times. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20 : 1), to obtain tert-butyl 3-((3R,4S)-4-(4-amino-3-(4-phenoxypheny1)-111-pyrazolo[3,4-djpyrimidin- I -y1)-3-fluoropiperidi n-1-y0azetidine-1-carboxylate (41e) (1.18 g, yield: 95%).
LCMS m/z = 560.3 [M+1]'.
Step 5:
1 -((3R,4S)-1-(azetidin-3-y1)-3-fluoropiperidin-4-y1)-3 -(4-phenoxypheny1)-1H-pyrazo lo [3 ,4-djpyrimi din-4-am ine (410 F
(R) 0 \ \i\r, N (s) N-VNH
Tert-butyl 3 -((3R,4 S)-4-(4-amino-3 -(4-phenoxyphenyI)-1H-pyrazolo [3 ,4-d]pyri m idin-1 -y1)-3 -fl uoropiperidi n-1 -yl)azetidine-l-carboxyl ate (41e) (800 mg, 1.43 mmol) was dissolved in 20 mL of DCM, and 8 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 h. Upon completion of the reaction, the system was directly concentrated under reduced pressure, and the residue was dissolved with 50 mL of 5 N sodium hydroxide solution, and extracted with 50 mL of DCM three times. The organic phase was washed with 30 mL of 1 N
sodium hydroxide solution twice, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, to obtain 1-((3R,4S)-1-(azetidin-3-y1)-3-fluoropiperidin-4-y1)-3 -(4-phenoxypheny1)-1H-pyrazolo [3 ,4-d]pyrimid in-4-amine (410 (0.57 g, yield: 87%).
LCMS m/z = 460.2 im-Fir.
Date Recue/Date Received 2021-09-09 Step 6:
tert-butyl 3-((3R,4S)-4-(4-amino-3 -(4-phenoxypheny1)-1H-pyrazolo [3,4-d]pyrimidin-1 -y1)-3-fl uoropiperi azeti dine] - -carboxy late (41g) H2N z N
:(R) 0 \\N'N' (s) =
\--N,Boc 1 -((3R,4S)-1 -(azetidin-3-y1)-3 -Iluoropiperidin-4-y1)-3-(4-phenoxypheny 0-1H-pyrazolo [3,4-d] pyrim i di n -4-am ine (410 (500 mg, 1.09 mmol) was dissolved in 30 mL of DCE, and tert-butyl 3-oxoazetidine- 1 -carboxylate (372 mg, 2.18 mmol) was added, the mixture was stirred at room temperature for 10 minutes, then sodium triacetoxyborohydride (0.93 g, 4.39 mmol) was added, and the mixture was stirred at room temperature overnight. To the reaction system was slowly added 50 mL of saturated sodium bicarbonate solution, and the mixed solution was extracted with 50 mL of DCM three times. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20 : 1), to obtain tert-butyl 3-((3R,4S)-4-(4-am ino-3-(4-phenoxypheny1)-1H-pyrazolo[3 ,4-di pyrimidin-l-y0-3-fluoropiperidin-1-y1)41,3'-bi azetidin]-1'-earboxylate (41g) (480 mg, yield: 72%).
LCMS m/z ---- 615.3 [M.+1]''.
Step 7:
1-((3R,4S)-1-([1,31-biazetidin]-3 -y1)-3-fluorop iperidin-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3 ,4-d]pyrimidin-4-amine (41h) H2N \ N
0 =
(s) --ONH
Tert-butyl 3-((3 R,4S)-4-(4-amino-3 -(4-phenoxypheny1)-1H-pyrazolo [3,4-Date Recue/Date Received 2021-09-09 d]pyrim idin-l-y1)-3 -fluo rop iperi din-l-y1)-[1,3t-biazeti din] -11-carboxylate (41g) (480 mg, 0.78 mmol) was dissolved in 20 mL of DCM, and 8 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 h. The reaction system was directly concentrated under reduced pressure, and the residue was dissolved with 30 mL of 5 N sodium hydroxide solution, and extracted with 30 mL of DCM three times. The organic phase was washed with 30 rriL of 1 N sodium hydroxide solution twice, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, to obtain 1-((3R,4 S)-1-( [1,3 T-biazetidinj-3 -y1)-3 -fluoropi peridin-4-y1)-3 -(4-phenoxyphenyI)-111-pyrazolo[3,4-d]pyrimidin-4-amine (41h) (0.40 g, yield: >
99%).
LCMS m/z = 515.2 [M+1] .
Step 8:
5-(3 -43R,4S)-4-(4-amino-3 -(4 -phenoxypheny1)-1H-pyrazolo [3 ,4-d]pyrimidin-1-y1)-3-fluoropiperidin-l-y1)-[ 1,3'-bi azeti din] -1 '-y1)-2-(2,6-dioxopiperidin-3 -yl)isoindo line-1,3 -dione (compound 41) N=--\

-.{R) Is 0 1 -((3 R,4 S)-1 -([1,31-biazeti din] -3 -y1)-3-fluoropiperi din -4-y1)-3 -(4-phenoxypheny1)-1H-pyrazo lo[3,4-d]pyrimidin-4-amine (41h) (300 mg, 0.58 mmol) was dissolved in 25 mL of DMSO, and 1.5 mL of DIPEA and 2-2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (242 mg, 0.88 mmol) were added, the reaction was stirred in an external bath at 80 C
for 5 h. The reaction solution was cooled to room temperature, added 50 nth of water, and extracted with 100 ml, of ethyl acetate. The organic phase was washed with mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichlorornethane/rn ethanol (v/v) = 15 1), to obtain 5-(34(3R,45)-4-(4-amino-3-(4-phenoxypheny1)-111-pyrazolo [3,4-d]pyrim idin- 1-y1)-3-fluoropi peridin- 1-y1)-[1,3'-biazeti din]-1'-y1)-2-(2,6-di oxopi peri din-3-yl)isoindoline-Date Recue/Date Received 2021-09-09 1,3-dione (compound 41) (280 mg, yield: 63%).
114 NMR (400 MHz, CDC13) 6 10.07 (s, 11-1), 8.39 (s, 11-1), 7.68 - 7.60 (m, 31-1), 7.41 - 7.34 (in, 2H), 7.19 - 7.04 (m, 5H), 6.78 (d, 1H), 6.51 (dd, 1H), 5.86 (brs, 2H), 5.18- 5.00 (m, 1H), 4.98 - 4.81 (m, 2H), 4.08 - 4.00 (m, 2H), 3.92 - 3.84 (m, 2H), 3.74 - 3.66 (m, 1H), 3.66 - 3.56 (m, 2H), 3.26 - 2.95 (m, 6H), 2.90 - 2.65 (m, 3H), 2.46 -2.29 (m, 1H), 2.28 -2.17 (in, 1H), 2.16 -2.05 (m, 2H).
LCMS m/z = 771.3 [M+1]+.
Example 42:
5-(34(3R,4S)-4-(4-amino-3-(4-phenoxypheny1)-111-pyrazolo[3,4-d]pyrimidin-I -y11-3-fluoro-[1,4'-bipiperidin]-1'-y1)azetidin-1-y1)-2-(2,6-dioxopiperidin-y1)isoindoline-1,3-dione (compound 42) H2N N.,-_-õ, E
R) C5 N ei \---N
"=-.
--- ,(' \O
H2N N'--, 2N , \
N
F Sip F Step 2 E swp i \ - (RI
-1.- 0 N 17,-7---1 1"- 0 ,(s) NH 6 .....,.....N a 41d 42a Boc 42b H2N , N'-'1 H2N r\L----\
\ , N \ N
-1/ _ titep .1 -r t R.
Step 5 0 \N-N, F,!1)6µ1j....; ____________________________ to.
N ' a (-4 0 ....---N--------.._.,.N.,.c....\
42c \-µ 42d \--NH
N.
H2N -p F
iõ.K = \N'N'" . F') N.........-----1 -_, .- ---k -uN ,, 0 _0\/\\_NI-4 Compound 42 Date Recue/Date Received 2021-09-09 Step I:
tert-butyl (3R,4S)-4 -(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-d]pyrimidin-1 -y1)-3-fluoro-[1,4'-bipiperidine]-1'-carboxy late (42a) /
0 \ ,R1) (5) 1 -((3R,4S)-3 -fluoropiperidi n-4-y1)-3-(4-phenoxypheny1)-11-1 -pyrazolo [3,4-d]pyrimidin-4-amine (41d) (0.9 g, 2.23 mmol) was dissolved in 35 rilL of DCE, and tert-butyl 4-oxopiperidine-1-earboxylate (887 mg, 4.46 minol) was added, the mixture was stirred at room temperature for 10 minutes, then sodium triacetoxyborohydride (1.89 g, 8.92 mmol) was added, and the mixture was stirred at room temperature overnight. To the reaction solution was slowly added 50 mL of saturated sodium bicarbonate solution, and the mixed solution was extracted with 50 roL of DCM three times. The organic phase was washed with 50 inL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20 : 1), to obtain tert-butyl (3R,4S)-4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-d]pyrimidi n-l-y1)-3-fluoro- [1,4i-bipiperidine]- F-earboxylate (42a) (1.08 g, yield: 83%).
LCMS m/z 588.3 [NI
Step 2:
1 -43R,45)-3-fluoro-[1,4'-bipiperidin]-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (42b) N
NH
Tert-butyl (3R,4S)-4-(4-am ino-3-(4-phen oxyph eny0-1H-pyrazolo[3,4-Date Recue/Date Received 2021-09-09 d]pyri midin-1 -y1)-3- fluoro- [1,4'-bipiperi dine]-1'-carboxylate (42a) (800 mg, 1.36 mmol) was dissolved in 30 mL of DCM, and 10 n-iL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 h. Upon completion of the reaction, the reaction system was directly concentrated under reduced pressure, and the residue was dissolved with 50 mL of 5 N sodium hydroxide solution, and extracted with nit of DCM three times. The organic phase was washed with 50 mL of 1 N sodium hydroxide solution twice, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain 14(3R,4S)-3-fluoro-[1,4'-hipiperidin]-4-y1)-3-(4-phenoxypheny1)-111-pyrazolo[3,4-d]pyrimidin-4-amine (42h) (600 mg, yield: 91 /0).
LCMS m/z = 488.3 [M+1] .
Step 3:
tert-butyl 3 -43R,4S)-4 -(4-amino-3 -(4-phenoxypheny1)-1H -pyrazolo [3,4 -d]pyrimidin-1 -yI)-3 -fluoro-[1,4'-bipiperidin] -1 t-yl)azetidine-1 -carboxyl ate (42c) H2N, 1/µ

(s) 41, Boc 1-((3R,4S)-3 -fluoro41,4t-bipiperidin]-4-y1)-3-(4-phenoxypheny1)-1I I-pyrazolo [3,4 pyri midin -4-amine (42b) (550 mg, 1.13 mmol) was dissolved in mL of DCE, and tert-butyl 3-oxoazetidine- 1 -carboxylate (380 mg, 2.22 mmoi) was added, the mixture was stirred at room temperature for 10 minutes, then sodium triacetoxyborohydride (0.95 g, 4.48 mmol) was added, and the mixture was stirred at room temperature overnight. To the reaction system was slowly added 50 mL of saturated sodium bicarbonate solution, and the mixed solution was extracted with 50 mL of DCM three times. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichlorornethane/methanol (v/v) = 20 : 1), to obtain tert-butyl 3-((3R,4S)-4-(4-amino-3-(4-phenoxypheny1)- I H-pyrazolo [3 ,4-dl pyrim idin -1-y1)-3-fluoro-[1,4'-Date Recue/Date Received 2021-09-09 bipiperidin]-11-yl)azetidine-1-carboxylate (42c) (620 mg, yield: 85%).
LCMS m/z = 643.4 [M+1]+.
Step 4:
(3R,4S)- F-(azetidin-3-y1)-3-f1uoro-[1,4'-bipiperidin 1-4-3/1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (42d) N

(S) = (R) H
Tert-butyl 3-43R,4S)-4-(4-ami no-3-(4-phenoxyphenyI)-1H-pyrazo lo [3,4-d]pyrimidin-l-y1)-3-fluoro-[1,4'-bipiperidin] -1'-yl)azetidine-1-carboxyl ate (42c) (580 mg, 0.90 mmol) was dissolved in 20 mL of DCM, and 8 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 h. The reaction system was directly concentrated under reduced pressure, and the residue was dissolved with 30 rnL of 5 N sodium hydroxide solution, and extracted with 30 nil.
of DCM three times. The organic phase was washed with 30 mL of 1 N sodium hydroxide solution twice, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, to obtain 1-((3R,4S)-1'-(azetidin-3-y1)-3-fluoro-[1,4'-bipiperidin]-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (42d) (480 mg, yield: 98%).
LCMS ni/z = 543.3 [M+1].'..
Step 5:
5 -(3-((3R,4S)-4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo [3 ,4-d]pyrimidin-1-y1)-3-fluoro-[1,4'-bipiperidin]-1'-yl)azetidin-1-y1)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (compound 42) Date Recue/Date Received 2021-09-09 z N
õ (R) 1-((3R,4S)-1`-(azetidin-3-y1)-3-fluoro41,4'-bipiperidin]-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (42d) (300 mg, 0.55 mmol) was dissolved in 25 MI, of DMSO, and I .5 ml, of DIPEA and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (sec WO 2017197056 for the synthetic method) (229 mg, 0.83 mmol) were added, the reaction was stirred in an external bath at 80 C
for 5 h. The reaction solution was cooled to room temperature, added 50 nriL
of water, and extracted with 100 mL of ethyl acetate. The organic phase was washed with mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) ----- 15 : 1), to obtain 5-(34(3R,4S)-4-(4-amino-3-(4-phenoxypheny1)- I H-pyrazolo[3,4-d]pyrimidin- I -y1)-3-fluoro-[1,4'-bipiperidin]-1'-yl)azetidin-l-y1)-2-(2,6-dioxopiperidin-3-ypisoindoline-1,3-dione (compound 42) (340 mg, yield: 77%).
1H NMR (400 MHz, CDC13) 6 9.63 - 9.46 (m, I H), 8.39 (s, 1H), 7.68 - 7.61 (m, 3H), 7.41 - 7.34 (m, 2H), 7.20 - 7.04 (m, 511), 6.79 (d, 1H), 6.52 (dd, 111), 5.78 (brs, 2H), 5.23 - 5.00 (m, 1H), 4.97 - 4.77 (m, 2H), 4.13 - 4.06 (m, 2H), 3.93 -3.84 (m, 211), 3.42 - 3.29 (m, 211), 3.27 - 3.14 (m, HI), 3.08 - 2.92 (m, 311), 2.92 -2.65 (m, 4H), 2.65 -2.46 (m, 2H), 2.18 - 2.06 (m, 2H), 2.02 - 1.84 (m, 4H), 1.76 - 1.61 (m, 2H).
LCMS m/z = 799.3 [NI 1 ]t Example 43 54343- [(3S,4S)-444-amino-3-(4-phenoxyphenyl)pyrazolo [3,4-d]pyrirnid in-1 -y11-3-fluoro-1 -piperidyl] azetidin- I -yli azetidin- I -y11-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (compound 43) Date Recue/Date Received 2021-09-09 N--.\\
H2N 5, r/ N-._\
(:)"._ \,N--<-",, \,,,N / \

o 0 N

N.- N.

-t H2N1b,\N
F.1,1.3..1",,k, SEep I , F.s, r.,11.----, -A-00,<- Step 2 \N, N,,....,Fc6; -rn 3 o-07/ -4 IN,F.:3' -D.- 0 HO f.R..--) Ms0 (4"i'= ,NH
NO
43a 43b a Cs) 6 --f 43c 0,.i< 43d N.---,,, , I i2N--- \ iN F I fzI4 \ IN F
H2N1.?
(2 F
(S) Siep 4 81 'Step n --- --. N=
, \N-N.' (6) '---...N-IµI'= 1 \ 1 '' 0 0 ,,,, o 435 43f 1\1.-=\
\ F
H2N-,N F
.......m [12N / N /
sr (s) . (s) A . 1,1'N. = s) N'N' 881)8 \
0 43h .--c:1\1H \- / rompoum143 Step 1:
tert-butyl (3S,4R)-3-fluoro-4-methylsulfonyloxy-piperidine-l-carboxylate (43b) F
Nil ACr<
wi., ASx-, f-(R001-2 ) Tert-butyl (3S,4R)-3-fluoro-4-hydroxypiperidine- 1-carboxylate (43a) (6.0 g, 27.39 mmol) was dissolved in 30 mL of dichloromethane, and DIPEA (7.06 g, 54.62 mmol) was added, then methanesulfonyl chloride (0.376 g, 3.28 mmol) was slowly added dropwise. Upon completion of the addition, the mixture was stirred at room temperature for 2 h. The reaction solution was quenched with 40 mL of water, and extracted with 100 mL of DCM three times. The organic phase was washed with mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column Date Recue/Date Received 2021-09-09 chromatography (petroleum ether/ethyl acetate (v/v) = 5 : 1), to obtain tert-butyl (3S,4R)-3-fluoro-4-methylsulfonyloxy-piperidine-1-earboxylate (43b) (7.97 g, yield:
98%).
Step 2:
tea-butyl (3S,4S)-444-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-l-y1]-3-fluoto-piperid inc-l-carboxyl ate (43c) N
0 -Nõ (s) N =
111. ,N y.10 Tert-butyl (3S ,4R)-3 -fluoro-4 -methylsulfonyloxy-piperidine-l-carboxylate (43b) (2.45 g, 8.25 mmol) and 3-(4-phenoxypheny1)-111-pyrazolo[3,4-d]pyrimidin-4-amine (1.0g. 3.30 mmol) was dissolved in 20 mL of DMF, and cesium carbonate (2.14 g, 6.57 mmol) was added, the reaction was stirred at 100 C for 7 h. The reaction was cooled to mom temperature, and the reaction system was added 50 ml, of water, and extracted with 100 mL of ethyl acetate three times. The organic phase was washed with 100 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) ¨ 15 : 1), to obtain tert-butyl (3 S ,4S)-4 -[4-ami no-3 -(4-phenoxyphenyl)pyrazolo [3 ,4 dipyrimidin-l-y11-3-fluoro-piperidine-l-carboxylate (43c) (0.9 g, yield: 54%).

LCMS m/z = 505.3 [M+1]+.
Step 3:
1 -[(3 S,4S)-3 -fluoro-4-piperidy1]-3 -(4-phenoxyphenyl)pyrazolo [3, 4-dipyrimidin-4-amine (43d) N-, N
0 -Nõ
N =
(5) Date Recue/Date Received 2021-09-09 Tert-butyl (3S,4S)-444-amino-3-(4-phenoxyphenyppyrazolo[3,4-d]pyrimidin-1-y1]-3-fluoro-piperidine-1-carboxylate (43c) (0.9 g, 1.79 mmol) was dissolved in 20 mL of DCM, and 5 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 h. The reaction system was directly concentrated under reduced pressure, and the residue was dissolved with 60 mL of 5 N sodium hydroxide solution, extracted with 100 naL of dichloromethane three times, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, to obtain [(3S ,4S)-3 -fluoro-4-piperidy1]-3 -(4-phenoxyphenyl)pyrazolo[3 ,4-d]pyrimidin-amine (43d) (0.7 g, yield: 97%).
LCMS m/z = 405.3 [M+1] .
Step 4:
tert-butyl 34(3 S,4S)-444-arnino-3 -(4-phenoxyphenyl)pyrazo lo [3,4 -d]pyrimidin-1 -y11-3 -fluoro-1-piperidyflazetidine-1 -carboxylate (43e) N--=\

(s) N (s) Si NB
1 -[(3 S,4S)-3-fluoro-4 -piperidy1]-3 -(4-phenoxyphenyl)pyrazolo [3,4 -dlpyrimidin-4-amine (43d) (0.7g. 1.73 mmol) was dissolved in 35 mL of DCE and 5 mL of DMSO, and tert-butyl 3-oxoazetidine-1-carboxylate (542 mg, 3.17 mmol) was added, the mixture was stirred at room temperature for 10 minutes, then sodium triacetoxyborohydride (1.68 g, 7.93 mmol) was added, and the mixture was stirred at room temperature overnight. To the reaction solution was slowly added 30 mL of saturated sodium bicarbonate solution, and the mixed solution was extracted with 50 mL of ethyl acetate three times. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20 : 1), to obtain tert-butyl 3-[(3S,4S)-4-[4-amino-3 -(4-phenoxyphenyl)pyrazolo [3,4-d]pyrimidin-1-y11-3-fluoro-1 -p iperidyl jazetidin e- 1 -carboxylate (43e) (800 mg, yield: 83%).
Date Recue/Date Received 2021-09-09 LCMS miz = 560.3 [M+1]t Step 5:
1 -[(3 S,4S)- 1 -(azetidin-3-y1)-3 uoro-4-piperidy1]-3-(4-phenoxyphenyl)pyrazolo [3 ,4-dipyri mi din-4-amine (431) F
(s) 0 (S) Tert-butyl 3 -[(3 S ,45 )-414-amino-3 -(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin- 1 -y1]-3 -fluoro- 1 -pip eridyliazetidi ne- 1 -carboxylate (43e) (500 mg, 0.89 mmol) was dissolved in 20 mL of DCM, and 5 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 h. Upon completion of the reaction, the system was directly concentrated under reduced pressure, and the residue was dissolved with 50 mL of 5 N sodium hydroxide solution, and extracted with 50 mL
of DCM three times. The organic phase was washed with 30 mL of 1 N sodium hydroxide solution twice, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, to obtain 1-[(3S,4S)-1-(azetidin-3-y1)-3-fluoro-4-piperidyli-is 3-(4-phenoxyphenyl)pyrazolo[3,4-djpyrimidin-4-amine (430 (0.4 g, yield:
98%).
LCMS ni/z = 460.2 [M+1]+.
Step 6:
tert-butyl 3-[3-[(3S,4S)-4- [4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-cl]pyrim idin- 1 -yl] -3-fluoro- 1 -piperidyti azetidin- 1 -yl] azetidine- 1 -carboxylate (43g) N=

(s) ,Nf N s) N80c 1 -[(3 S,4S )- 1 -(azetidin-3 -y1)-3 -fluoro-4 -piperidyl] -3 -(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine (430 (0.4 g, 0.87 mmol) was dissolved in 25 mL of DCE and 2 mL of DMSO, and tert-butyl 3-oxoazetidine-1-Date Recue/Date Received 2021-09-09 carboxylate (485 mg, 2.83 mmol) was added, the mixture was stirred at room temperature for 10 minutes, then sodium triacetoxyborohydride (1.12 g, 5.28 mmol) was added, and the mixture was stirred at room temperature overnight. To the reaction system was slowly added 60 mL of saturated sodium bicarbonate solution, and the mixed solution was extracted with 60 mL of ethyl acetate three times. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) =
20:
1), to obtain tert-butyl 3434(3S,4S)-444-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-y1]-3-fluoro-l-piperidyl]azetidin-1-yliazetidine-1-carboxylate (43g) (450 mg, yield: 84%).
LCMS m/z = 615.3 [M+1].
Step 7:
1-[(3S,4S)-141-(azetidin-3-ypazetidin-3-y1]-3-fluoro-4-piperidy1]-3 -(4-phenoxyphenyl)pyrazo ,4-d]pyrimidin-4-amine (43h) Nz H2N /1.1 F
(s) Tert-butyl 3-[3 -[(3 S,4S)-4-[4-amino-3 -(4-phenoxyphenyl)pyrazolo[3 ,4-d]pyrimidi n-1 -yl] -3 -fluoro-l-piperidyl]azetidi n-l-yl]azetidi ne-1 -carboxy late (43g) (400 mg, 0.65 mmol) was dissolved in 20 mL of DCM, and 4 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 h. The reaction system was directly concentrated under reduced pressure, and the residue was dissolved with 30 mL of 5 N sodium hydroxide solution, and extracted with 30 mL
of DCM three times. The organic phase was washed with 30 mL of 1 N sodium hydroxide solution twice, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, to obtain 14(3S,4S)-141-(azetidin-3-yl)azetidin-3-y1]-fluoro-4-piperidy1]-3-(4-phenoxyphenyppyrazolo[3,4-d]pyrimi din-4-am inc (43h) (0.33 g, yield: 99%).
Date Recue/Date Received 2021-09-09 LCMS m/z = 515.2 [M+1].
Step 8:
54343- [(3S,4S)-444-amino-3 -(4-phenoxyphenyl)pyrazolo [3 ,4-d]pyrimidin-1-yl jazetidin- 1 -yl jazetidin- 1 -y1J-2-(2,6-dioxo-3 piperidyl)isoindoline-1,3-dione (compound 43) N=--\

(s) N

14(3 S,4S)-1 -[1 -(azetidin-3 -yl)azetidin-3 -yl] -3-fluoro -4-piperidyI]-3 -(4 -phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine (43h) (0.33 g, 0.64 mmol) was dissolved in 25 int of DMSO, and 3 mL of DIPEA and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-clione (see WO 2017197056 for the synthetic method) (352 mg, 1.28 'limo') were added, the reaction was stirred in an external bath at 80 C for 5 h. The reaction solution was cooled to room temperature, added 50 int of water, and extracted with 100 mL of ethyl acetate. The organic phase was washed with mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) ----- 20 : 1), to obtain 5-[3-[3-[(3S ,4S)-4-[4- amino-3 -(4-phenoxyphenyl)pyrazolo [3 ,4-d]pyrimidin-l-y1]-3 -fluoro-1-p iperidyljazetidin- I -yliazetidin-l-y1]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-clione (compound 43) (125 mg, yield: 25%).
11-1 NMR (400 MHz, CDC13) 6 9.61 (s, 1H), 8.41 (s, 1H), 7.69 - 7.61 (m, 3H), 7.43 - 7.35 (m, 2H), 7.21 - 7.05 (m, 514), 6.79 (d, 1H), 6.53 (dd, 1H), 5.80 (brs, 2F1), 5.35 - 5.13 (m, 1H), 4.97 - 4.83 (m, 2H), 4.09 - 4.01 (m, 2H), 3.93 - 3.85 (m, 2H), 3.75 - 3.55 (rn, 3H), 3.29 - 3.06 (m, 4H), 2.92 - 2.65 (m, 4H), 2.53 - 2.39 (m, 11-1), 2.22 - 2.05 (m, 4H).
LCMS m/z = 771.3 [M-F 1 ].
Date Recue/Date Received 2021-09-09 Example 44:
5-(343S,4S)-4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-1-y1)-3-fluoro[1,41-bipiperidin]-11-y1)azetidin-1-y1)-2-(2,6-dioxopiperidin-3-y1)isoindoline-1,3-dione (compound 44) H2N N-_-_-\
¨ F
--...,....õ-N...õ..---) ---,-N,1,\

F . F
Swp 1 \ ,N, F(s) Stcp 2 Sig, 3 aS>
NH a is) Nn -43d 44a =-.....õ-N.Boc 44b N., \ H2N N., \
H2N , , F

õ,õ..40 \ - N,..-ks_i.) SM., 5 c--1 N c, 'CIN Step4 7 N --,,, N,Boc 44c 44d \ / N
¨ 11 Fcs) ..,,KC) Campoand Step 1:
tert-butyl (3S,4S)-444-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,41-cl]pyrimidin-1-0-3-fluoro-[1,4cbipiperidine]-1'-earboxylate (44a) Date Recue/Date Received 2021-09-09 /N
0 \N )1 (S) N
14(3 S,4S)-3 -fluoro-4 -piperi dy1]-3 -(4-phenoxyphenyl)pyrazol o[3 ,4-d]pyrimidin-4-amine (43d) (800 mg, 1.98 mmol) was dissolved in 35 mL of DCE, and tert-butyl 4-oxopiperidine-l-carboxylate (787 mg, 3.95 mmol) was added, the mixture was stirred at room temperature for 10 minutes, then sodium triacetoxyborohydride (1.68 g, 7.93 mmol) was added, and the mixture was stirred at room temperature overnight. To the reaction solution was slowly added 30 rriL
of saturated sodium bicarbonate solution, and the mixed solution was extracted with 30 mL of DCM three times. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) ----- 20 : 1), to obtain tcrt-butyl (3S,4S)-4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-1-y1)-3-fluoro-[1,4'-bipiperidinej-lt-carboxylate (44a) (970 mg, yield: 83%).
is LCMS m/z = 588.3 [M+1]+.
Step 2:
1-((3S,4S)-3-fluoro-[1,4`-bipiperidin]-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (44b) /N

(s) NH
Tert-butyl (3 S,4S)-4-(4-amino-3 -(4-phenoxypheny1)-1H-pyrazo lo[3 ,4-d]pyrimidin-1 -yI)-3 -fluoro- [1,4t-bipiperidinej- I t-carboxylate (44a) (650 mg, 1.11 mmol) was dissolved in 20 mL of DCM, and 8 mL of trifluoroacetie acid was added, the mixture was stirred at room temperature for 4 h. Upon completion of the reaction, Date Recue/Date Received 2021-09-09 the system was directly concentrated under reduced pressure, and the residue was dissolved with 30 mL of 5 N sodium hydroxide solution, and extracted with 30 nit of DCM three times. The organic phase was washed with 30 mL of 1 N sodium hydroxide solution twice, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain 14(3S,4S)-3-fluoro-[1,4'-bipiperidin]-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (44b) (540 mg, yield: >
99%).
LCMS m/z = 488.3 [M+1] .
Step 3:
tert-butyl 3 -((3 S,4S)-4-(4-amino-3 -(4-phen oxyphenyI)-1H-pyrazolo[3 ,4-d]pyrimidin- I -y1)-3 -fluoro-[1,4'-bipiperidin] -1`-yl)azetidine-l-carboxylate (44c) N
(3) N
N
' Boc 1 -((3 S,4S)-3 uoro-[1,4`-bipiperidin]-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (44b) (500 mg, 1.03 mmol) was dissolved in 30 mL of DCE, and tert-butyl 3-oxoazetidine- 1 -carboxylate (350 mg, 2.05 mmol) was added, the mixture was stirred at =room temperature for 10 minutes, then sodium triacetoxyborohydride (870 mg, 4.10 mmol) was added, and the mixture was stirred at room temperature overnight. To the reaction system was slowly added 30 mi, of saturated sodium bicarbonate solution, and the mixed solution was extracted with 30 mL of DCM three times. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichlorometbane/methanol (v/v) = 20 : 1), to obtain tert-butyl 3-((3S,4S)-4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d] pyrimidin-1-y1)-3-fluoro-[1,4'-bipiperidin]-r-yl)azetidine-1-carboxylate (44c) (560 mg, yield: 85%).
LCMS m/z = 643.4 {M-F1].
Date Recue/Date Received 2021-09-09 Step 4:
14(3S,4S)-1'-(azetidin-3-y1)-3-fluoro-[1,4'-bipiperidin]-4-y1)-3-(4-phenoxy-pheny1)-1H-pyrazolo[3,4-djpyrimidin-4-aminc (44d) z N
\
\--NH
1-eft-butyl 34(3S,4S)-4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-d]pyrimidin-1-y1)-3-fluoro41 ,4'-bipiperidin1-1`-yl)azetidine-1 -carboxyl ate (44c) (500 mg, 0.78 mmol) was dissolved in 20 mL of DCM, and 8 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 h. The reaction system was directly concentrated under reduced pressure, and the residue was dissolved with 30 mL of 5 N sodium hydroxide solution, and extracted with 30 mL
of dichloromethane three times. The organic phase was washed with 30 mL of 1 N

sodium hydroxide solution twice, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, to obtain 1 -((3S,4S)- l'-(azetidin-3-y1)-3-1-luoro-[1,4'-bipiperidinj-4-y1)-3-(4-phenoxy-phenyl)- 1H-pyrazolo [3,4-d]pyrimidin-4-amine (44d) (420 mg, yield: > 99%).
LCMS na/z = 543.3 [M+1r.
Step 5:
5-(34(3S,4S)-4-(4-am ino-3-(4-phenoxyphenyI)-1 H-pyrazolo [3 ,4-d]pyrim id in-1-y1)-3-fluoro-[1,41-bipiperidini -1'-yl)azetidin-l-y1)-2-(2,6-dioxopiperidin-yl)isoindoline-1,3-dione (compound 44) N.
H2N , N
0 -N, N
Inkrn NH

1 -((3S,4S)-1'-(azetidin-3-y1)-3-fluoro-[ I ,4'-bipiperidin]-4-y1)-3-(4-Date Recue/Date Received 2021-09-09 phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (44d) (310 mg, 0.57 mmol) was dissolved in 25 mL of DMSO, and 1.5 mL of D1PEA and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (236 mg, 0.86 mmol) were added, the reaction was stifled in an external bath at 80 C
for 5 h. The reaction solution was cooled to room temperature, added 50 mL of water, and extracted with 100 rriL of ethyl acetate. The organic phase was washed with 100 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 15 : 1), to obtain 5-(34(3S,4S)-1.0 __ 4-(4-amino-3 -(4-ph enoxypheny1)-1H-pyrazolo[3,4-d]pyrim idi n-1-y1)-3-fluoro- [I,4'-bipiperidin]- I '-yl)azetidin- I -y1)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (compound 44) (310 mg, yield: 68%).
'H NMR (400 MHz, CDC13) i3 9.49 (s, 1H), 8.41 (s, 1H), 7.71 - 7.58 (m, 3H), 7.43 - 7.33 (m, 2H), 7.22 -7.11 (m, 3H), 7.11 -7.03 (m, 2H), 6.83 -6.74 (m, 1H), 6.57 -6.47 (m, 111), 5.78 (brs, 2H), 5.33 -5.09 (m, 1H), 4.98 -4.79 (m, 2H), 4.16 -4.04 (in, 2H), 3.96 - 3.85 (in, 2H), 3.46 -3.31 (in, 2H), 3.07 -2.91 (in, 3H), 2.91 -2.65 (m, 3H), 2.57 - 2.34 (m, 4H), 2.18 - 1.93 (m, 4H), 1.92 - 1.82 (in, 2H), 1.74 -1.58 (m, 2H).
LCMS m/z = 799.3 [M+
Example 45:
5-(3-((3 S,4R)-4-(4-amino-3-(4-phenoxypheny1)-1H -pyrazolo[3,4-c]pyrim i di n-1-y1)-3-fluoro-[1,4'-bipiperidin]-1'-yl)azetidiii- I -y1)-2-(2,6-dioxopiperi din-3-ypisoindoline-1,3 -dione (compound 45) N-=\

Date Recue/Date Received 2021-09-09 N, H2N I\ H27 k---- \ N__-, I .\i_i_\
\ ,N \ ,,, N \ ,N
F Step I Step 2 ÷= F , , 0 Al- NI', 0!1 -j.-- l'IN (R) s ,,,,N..õ,õNH a NiO
38d 45a 13oc 45b c,õ,-N. 0,0 1---.õ-NH
H2N \
_.4 H2N--\ N F _4µN , F
0 's , µ4...cil sop s _____________________________________________________________________ 7 N ,R, 6 .......,N,---..Th 0 N.,...õ----õ, ,...,..õ.: N
45c \----N'Boo 45d \--NH

--,õ-N\ 0 Compound 0 Step I:
tert-butyl (3S,4R)-4-(4-ami no-3-(4-phenoxyphenyI)-1H-pyrazolo [3,4-d]pyrimidin-1-yI)-3-fluoro- [1,4'-bipiperid ine]-1'-carboxylate (45a) H2N _--\
\ / N
F

(R) Boc 14(3S,4R)-3-fluoro-4-piperidyl j-3-(4-phenoxyphenyl)pyrazo1o[3,4-djpyrimidin-4-amine (38d) (1.1 g, 2.72 mrnol) was dissolved in 35 mL of DCE, and tert-butyl 4-oxopiperidine-l-carboxylate (1.08 g, 5.43 mmol) was added, the mixture was stirred at room temperature for 10 minutes, then sodium triaeetoxyborohydride (2.31 g, 10.90 mmol) was added, and the mixture was stirred at room temperature overnight. To the reaction solution was slowly added 50 rnL of saturated sodium bicarbonate solution, and the mixed solution was extracted with 50 mL of DCM
three times. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product was Date Recue/Date Received 2021-09-09 separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20: 1), to obtain tert-butyl (3S,4R)-4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazo1o[3,4-d]pyrimidin-1-y1)-3-fluoro-[1,4`-bipiperidine]
-1.1-carboxylate (45a) (1.4g. yield: 88%).
LCMS m/z = 588.3 [M-F-1]-1.
Step 2:
1-((3S,4R )-3-fluoro-[1,4t-bipiperidin]-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (45b) /
¨0/ N
N H
Tert-butyl (3 S ,4R)-4-(4-amino -3 -(4-phenoxypheny1)-1H-pyrazolo[3 ,4-d]pyrimidin-1 -y1)-3 -fluoro- [1 ,4'-bip iperi din e]-1'-carboxylate (45a) (1.4 g, 2.38 mmol) was dissolved in 30 mL of DCM, and 10 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 h. Upon completion of the reaction, the system was directly concentrated under reduced pressure, and the residue was dissolved with 50 mL of 5 N sodium hydroxide solution, and extracted with 50 mL
of DCM three times. The organic phase was washed with 30 mL of 1 N sodium hydroxide solution twice, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain 1-( (3 S,4R)-3 -fluoro-[1,4'-b ip iperidin]-4-y1)-3 -(4-phenoxypheny1)-11-1-pyrazolo[3,4-d]pyrirnidin-4-amine (45b) (1.2 g, yield: >
99%).
LCMS m/z = 488.3 [M 1]+.
Step 3:
tert-butyl 3 -((3 S,4R)-4-(4-amino-3 -(4-phenoxyphenyI)-1H-pyrazolo [3 ,4-c]pyrim idin-1 -y1)-3 -fluoro-[1,4'-bipiperidin] -1`-y Dazetidine-1 -carboxyl ate (45c) Date Recue/Date Received 2021-09-09 /

(R) =
Boc 1 -((3S,4R)-3 -fluoro-[1,4'-bipiperidinj-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d] pyrimidin-4-amine (45b) (600 mg, 1.23 mmol) was dissolved in mL of DCE, and tert-butyl 3-oxoazetidine- 1 -carboxylate (421 mg, 2.46 mmol) was added, the mixture was stirred at room temperature for 10 minutes, then sodium triacetoxyborohydride (1.04 g, 4.91 mmol) was added, and the mixture was stirred at room temperature overnight. To the reaction system was slowly added 50 mL of sodium bicarbonate solution, and the mixed solution was extracted with 50 mL
of DCM three times. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20 : 1), to obtain tert-butyl 34(3S,4R)-4-(4-amino-3-(4-phenoxypheny1)- 1H-pyrazolo [3 ,4-d] pyrimidin-l-y1)-3- fluoro-[1,4'-bipiperidin]-1'-ypazetidine-1-carboxylate (45c) (700 mg, yield: 89%).
is LCMS m/z = 643.4 [M+1]+.
Step 4:
1-((3S,4R)-1`-(azetidin-3-y1)-3-fluoro-[1,4'-bipiperidin]-4-y1)-3-(4-phenoxypheny1)-11-1-pyrazolo[3,4-d]pyrirnidin-4-amine (45d) 4j\. N
(R) N
-VNH
Tert-butyl 3-((3S,4R)-4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-d]pyrimidin-1-y1)-3-fluoro-[1,4'-bipiperidin] -1'-yl)azetidine-l-carboxyl ate (45c) (600 mg, 0.93 annol) was dissolved in 20 inL of DCM, and 8 mL of trifluoroacetic Date Recue/Date Received 2021-09-09 acid was added, the mixture was stirred at room temperature for 4 h. The reaction system was directly concentrated under reduced pressure, and the residue was dissolved with 30 int of 5 N sodium hydroxide solution, and extracted with 30 nit of DCM three times. The organic phase was washed with 30 mL of 1 N sodium hydroxide solution twice, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, to obtain 1-((3S,4R)-1t-(azetidin-3-y1)-3-fluoro-[1,4`-bipiperidin]-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (45d) (0.44 g, yield: 87%).
LCMS m/z = 543.3 [M 1].
Step 5:
5-(3-((3S,4R)-4-(4-ami no-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-d] pyri mi di n-l-y1)-3-fluoro-[1,41-bipiperidin]-1'-y1)azetidin-1-y1)-2-(2,6-dioxopiperi din-ypisoindoline-1,3-dione (compound 45) N.=-\

{s/

1-((3S,4R)-1T-(azetidin-3-y1)-3-fluoro41,41-bipiperidini-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (45d) (300 mg, 0.55 mmol) was dissolved in 25 mL of DMSO, and 1.5 mL of DIPEA and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (229 mg, 0.83 mmol) were added, the reaction was stirred in an external bath at 80 C
for 5 h. The reaction solution was cooled to room temperature, added 50 mL of water, and extracted with 100 mL of ethyl acetate. The organic phase was washed with mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 15 : 1), to obtain 5-(3-((3S,4R)-4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-1-y1)-3-fluoro-[1,4'-bipi peridin]-1'-yl)azeti din- 1-y1)-2-(2,6-di ox opi peri di n-3-yl)i soindoline-1,3-di one (compound 45) (220 mg, yield: 50%).
Date Recue/Date Received 2021-09-09 111 NMR (400 MHz, CDC13) 6 9.37 (s, 111), 8.39 (s, 111), 7.68 - 7.60 (m, 311), 7.42 - 7.34 (m, 2H), 7.20 - 7.04 (m, 511), 6.79 (d, 111), 6.52 (dd, 1H), 5.74 (brs, 211), 5.23 - 5.02 (in, 1H), 4.97 -4.79 (in, 211), 4.14- 4.05 (in, 211), 3.94- 3.84 (m, 2H), 3.41 - 3.29 (m, 2H), 3.27 - 3.15 (m, 1H), 3.07 - 2.92 (m, 3H), 2.92 - 2.66 (m, 411), 2.65- 2.48 (m, 2H), 2.18- 2.06 (m, 211), 2.03- 1.84 (m, 4H), 1.75 - 1.61 (m, 2H).
LCMS ni/z ¨ 799.3 [M+1]'.
Example 46-1:
trans-5-(3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-1-y1)-3'-fluoro-[1,4'-bipiperidin]-1'-yl)azetidin-1-y1)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione-P1 (compound 46-1) N-, N

N E
N

0 or /N

N

NH

Date Recue/Date Received 2021-09-09 0 OH OMs N3 ----11--...---F Step I ..õ..-1-.,õ-F Step 2 F
_, ..- Step ----C.,--F Step 4 (cis) (cis) " i. (trans) -I., _____________________________ IN
-t\r- .1\1-I I ril 1\
Bicc Boc Boo Boo 46a 466 46c 46d ..)......õ..õ.F F F
(trans) Step 5 Step 6 ,....N.- -I-- 0-C\N (trar4J¨Boc ______________ 0 HO¨( N (trans)N¨BOC
LC
46e 46f 46g Step 7 F
411 _ci-\N (trans)N¨B C
Nsl\I
¨lb- Ts() ¨( \N (1,011*\)µ Step 8 N¨Boc / / _,,_ H2N / \ N
N-----,- ' 46h 0 F 46i M. 110 N----=-/
Formula 46i-a Step 9 -, F

--- 'N¨C
..-N-------/
Formula 46i-0 461-1 and 461-2 Date Recue/Date Received 2021-09-09 0 k, - old,,$)N¨Boc 10 \ z N
Step 11 ____________________________________________ t....- 0 \N,N----"Th 6 rans ,4 *I
46j NH
46i-1 1-12N \ H2N -1 N
0 \ N Step 12 0 \ _N
F F
-......._,N....1 -...._,N......ki 6 (trans) d 46k ....,..,.N,...õ.1 ....,...õ..N.,..,__7 Boc H2N¨ Nz-_-\
\ / N
Step 13 0 \NJ-N'"-------'1 F
_____________ r Formula 46-a ......õ...N...õ__\
\--N j4.0 0 tNE1N¨/ 0 N-_,-\ or \ / N 0 6 N 0õ).õ.., Formula 46-b Compound 46-1 Step 1:
cis-tert-butyl 3-fluoro-4-hydroxy-piperidine-1-carboxylate (46b) OH
}..,..õ....F
(cis) --, N"--Sec Tert-butyl 3-fluoro-tert-butyl 4-oxopiperidine-l-carboxylate (46a) (13.0 g, 59.8 mmol) was dissolved in 130 mL of anhydrous methanol, and sodium borohydride (4.52 g, 119.5 mmol) was slowly added. Upon completion of the addition, the mixture was stirred at room temperature for 30 minutes. The reaction solution was quenched with 60 mL of saturated ammonium chloride solution, and extracted with 200 mL
of Date Recue/Date Received 2021-09-09 dichloromethane. The organic phase was washed with 100 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4 : 1-7 : 3), to obtain cis-tert-butyl 341uoro-4-hydroxyl-s piperidine-1 -carboxylate (46b) (9.0 g, yield: 69%).
11-1 NMR (400 MHz, CDC13) 64.70 - 4.51 (in, 1H), 3.99 - 3.83 (in, 2H), 3.79 -3.60 (m, 1H), 3.52 - 3.33 (m, 1H), 3.25 - 3.10 (m, 1H), 1.95 (br.s, 1H), 1.89 -1.69 (m, 21-1), 1.46 (s, 9H).
Step 2:
Cis-tert-butyl 3-fluoro-4-methylsul fonyloxy-piperi dine-l-cathoxy I ate (46e) OMs (cis) 60c Cis-tert-butyl 3-fluoro-4-hydroxyl-piperidine-1-carboxylate (46b) (1.20 g, 5.47 minol) was dissolved in 12 mL of dichloromethane, and triethylamine (0.720 g, 7.12 mmol) was added, then methanesulfonyl chloride (0.940 g, 8.21 mmol) was slowly is added dropwise at 0 C. Upon completion of the addition, the reaction was carried out at 0 C for 30 min. At 0 C, to the reaction solution was added dropwise 10 mL
of saturated ammonium chloride solution to quench the reaction, until to room temperature. The liquid separation was conducted, the aqueous phase was further extracted with 20 mL of dichloromethane, and the organic phase was combined.
The organic phase was washed with 20 mL of saturated sodium chloride solution once, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, to obtain the crude product cis-tert-butyl 3-fluoro-4-methylsulfonyloxy-piperidine- 1 -carboxylate (46e) (1.60 g).
Step 3:
trans-tert-butyl 4- azido-3 -fl uoro-piperidine-l-carboxylate (46d) (trans>
Boc Date Recue/Date Received 2021-09-09 The above crude product cis-tert-butyl 3 -fluoro-4-methyl sul fonyl oxy-piperidin e-1 -carboxylate (46c) (1.60 g) was dissolved in 10 mL of DMF, and sodium azide (1.05 g, 16.2 mmol) was added. Upon completion of the addition, the reaction was stirred at 95 C for 5 h. The reaction solution was cooled to room temperature, added 10 nth of water, and extracted with 50 mL of ethyl acetate. The liquid separation was conducted, the organic phase was further washed with 20 nth of saturated sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =
9 : 1), to obtain trans-tert-butyl 4-azido-3-fluoro-piperidine- I -earboxylate (46d) (0.900 g, two-step yield calculated from compound 46b: 67%).
1H NMR (400 MHz, CDC13) 6 4.46 - 4.25 (m, 1H), 4.21 - 4.00 (in, 1H), 3.87 -3.77 (m, 1H), 3.71 - 3.59 (m, 1H), 3.19 - 2.97 (in, 2H), 2.06 - 1.94 (m, 1H), 1.59 -1.49 (m, 1H), 1.46 (s, 9H).
Step 4: trans-teii-butyl 4-amino-3-fluoro-piperidine-1-carboxylate (46e) (trans) Boc Trans-tert-butyl 4-azido-3-fluoro-piperidine-1-earboxylate (46d) (0.900 g, 3.68 mmol) was dissolved in 10 mL anhydrous ethanol, and 150 mg of 10% palladium carbon was added, the mixture was stirred under H2 atmosphere at room temperature for 16 h. The reaction solution was filtered off with suction, and the filtrate was concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) =

100 : 0-20 : 1), to obtain trans-tcrt-butyl 4-amino-3-fluoro-piperidine- 1 -carboxylate (46e) (0.500 g, yield: 62%).
1H NMR (400 MHz, CDCI3) 8 4.42 - 4,19 (in, 1H), 4.18- 3.92 (m, 2H), 2.98 -2.69 (m, 3H), 1.93 - 1.82 (in, 1H), 1.55 (br.s, 2H), 1.46 (s, 9H), 1.41 - 1.28 (m, IH).
Step 5:
trans-tert-butyl 3-fluoro-4-(4-oxo-l-piperidyl)piperidine-1-carboxylate (461) Date Recue/Date Received 2021-09-09 F
0-(\N N¨Boc / /
Pentan-1,4-dien-3-ol (5.0 g, 59.4 mmol) was dissolved in 50 mL of 1,2-dichloroethane, and 2-iodoxybenzoic acid (1BX) (33 g, 117.8 mmol) was added, the reaction was stirred at 70 C for 3 h. The reaction solution was cooled to room temperature, and filtered off with suction, and the filtrate was directly used in the next step.
Trans-tert-butyl 4-amino-3-fluoro-piperidine-1-carboxylate (46e) (3.6 g, 16.5 mmol) was dissolved in 10 mL of anhydrous methanol, and diisopropylethylamine (4.26 g, 33.0 mmol) was added, then the above filtrate was added, the reaction was to stirred at 70 C for 3 h. The reaction solution was cooled to room temperature, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =
4 : 1-2 : 3), to obtain trans-tert-butyl 3-fluoro-4-(4-oxo-1 -piperidyl)piperidine-1 -carboxylate (460 (4.0 g, yield: 81%).
1H NMR (400 MHz, CDC13) 6 4.61 -4.31 (in, 2H), 4.16 -4.00 (in, 1H), 3.06 -2.91 (m, 411), 2.87 - 2.66 (in, 311), 2.45 (t, 411), 1.90- 1.79 (in, 114), 1.60- 1.48 (m, 111), 1.46 (s, 91-1).
LCMS in/z ¨ 301.3 [M-Flr.
Step 6:
trans-tert-butyl 3-fluoro-4-(4-hydroxy-l-piperidyl)piperidine-l-carboxylate (46g) F
HO¨( \N (transN¨Boc Trans-tert-butyl 3 -fluoro-4-(4-oxo-l-pi peridyl)pi perid me-l-carboxylate (460 (4.0 g, 13.3 mmol) was dissolved in 40 mL of anhydrous methanol, and sodium borohydride (0.505 g, 13.3 rnmol) was added. Upon completion of the addition, the reaction was carried out at room temperature for 10 min. To the reaction solution was added dropwise 25 mL of saturated ammonium chloride solution to quench the reaction, and the resulted solution was extracted with 50 mi. of ethyl acetate twice.
Date Recue/Date Received 2021-09-09 The organic phase was combined, washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 100 : 0-9 : 1), to obtain trans-tert-butyl 3-fluoro-4-(4-hydroxy- 1 -piperidyppiperidine-1-carboxylate (46g) (3.2 g, yield: 80%).
1H NMR (400 MHz, CDC13) 6 4.65 - 4.40 (m, 1H), 4.38 - 4.22 (m, 1H), 4.09 -3.91 (m, 1H), 3.76 - 3.61 (m, 111), 2.99 - 2.39 (m, 7H), 2.00 - 1.71 (m, 3H), 1.65 -1.41 (m, 1211).
LCMS m/z = 303.3 [M+ Ir.
Step 7:
trans-tert-butyl 3-11 uoro-444-(p-tosyl oxy )-1-piperidyl]piperidine-1 -carboxylate (46h) ("n5>N1¨Boc Ts0 Trans-tert-butyl 3 -fluoro-4-(4-hydroxy-l-piperi dyl)piperi dine-1-carboxyl ate (46g) (1.80 g, 5.95 mmol) was dissolved in 18 mL of pyridine, and p-toluenesulfonyl chloride (2.27 g, 11.9 mmol) was added. Upon completion of the addition, the reaction was stirred at 70 C for 2 hours. The reaction solution was cooled to room temperature, and 30 mL of water and 60 mL of ethyl acetate were added. The liquid separation was conducted, and the organic phase was washed successively with mL of saturated sodium bicarbonate solution, 40 mL of 0.5 mol/L hydrochloric acid and 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, to obtain the crude product trans-tert-butyl 3-fluoro-4- [4-(p-tosyloxy)- I -p iperidyljpiperid inc-l-carboxyl ate (46h) (2.48 g).
Step 8:
trans-tert-butyl-4- [4-14-amino-3-(4-phenoxyphenyppyrazolo[3,4-d]pyrimidin-l-y11-1-piperidyl]-3-fluoro-piperidine-1-carboxylate (46i) Date Recue/Date Received 2021-09-09 Ki--Boc (trans N
H2N 'N
N./
3-(4-phenoxypheny1)- I H-pyrazolo[3,4-d]pyrimidin-4-amine (1.50 g, 4.95 minol) was dissolved in 10 ml., of DMF, and the above crude product tran s-tert-butyl 3-fluoro-4-[4-(p-tosyloxy)-1-piperidyl]piperidine- 1 -carboxylate (46h) (2.48 g) and cesium carbonate (3.24 g, 9.94 mmol) were successively added. Upon completion of the addition, the reaction was stirred at 60 C for 2 h. The reaction solution was cooled to room temperature, and 10 mL of water and 20 mL of ethyl acetate were added.
The liquid separation was conducted, and the organic phase was washed with 5 mi., of saturated sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) 100 : 0-50 : 1), to obtain trans-tert-butyl 4-1444-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-l-y1]-1-piperidy11-3-fluoro-piperidine-l-carboxylate (46i) (0.900 g, yield: 31%).
11-1 NMR (400 MHz, CI C13) 6 8.36 (s, 111), 7.69 - 7.62 (m, 2H), 7.43 - 7.35 (m, 211), 7.21 -7.11 (m, 3H), 7.11 - 7.05 (m, 2H), 5.64 (br.s, 21-1), 4.86 - 4.74 (m, 11-1), 4.69 - 4.46 (m, ill), 4.42 - 4.25 (m, 114), 4.12 - 3.94 (m, 114 3.19 - 3.03 (m, 211), 2.87 - 2.63 (m, 5H), 2.50 -2.34 (m, 2H), 2.12 - 2.01 (m, 211), 1.93 - 1.84 (m, 111), 1.63 - 1.50 (m, 114), 1.47 (s, 914).
Step 9:
trans-tert-butyl-4- [444-amino-3 -(4-phenoxyphenyl)pyrazolo[3,4-dipyri midi n-1-yI]-1-pipericly1]-3-fluoro-piperidine-l-carboxylate-P I (46i-1) trans-tcrt-buty1-4- [444-amino-3 -(4-phcnoxyphenyl)pyrazolo[3,4-d]pyrimid in-1-y1]- 1-piperidy11-3-fluoro-piperidine- 1-carboxylate-P2 (46i-2) Date Recue/Date Received 2021-09-09 H2N \N
and formula 461-a ' N
formula 46i-b Compounds 461-1 and 46i-2 were separated and prepared from compound 461 by means of high performance liquid chromatography. The preparation conditions were as follows:
instrument and preparative column: using MG IT preparative SFC (SFC-1) to prepare the liquid phase, preparative column model: ChiralPak IC, 250 x 30 mm 1.D., 1 0 pm.
Preparation method: the crude product was dissolved with methanol/dichloronnethane, to prepare into a sample solution.
Mobile phase system: sCO2/ isopropanol (containing 0.1% ammonia water), isocratic elution: sCO2/ isopropanol (containing 0.1% ammonia water) = 55/41 Flow rate: 80 mL/min Analysis method for compounds 46i-1 and 46i-2:
Instrument: Waters UPC2 analytical SFC (SFC-H) Chromatographic column: CHIRALPAK IC
Specification: 150 mm x 4.6 mm, 3 pm Mobile phase A: 5CO2 Mobile phase B: isopropanol (containing 0.05% diethylamine) Column temperature: 35 C
Flow rate: 2.5 mL/min Wavelength: 254 nm Isocratic elution: mobile phase A: 13 = 60 : 40.
Date Recue/Date Received 2021-09-09 Retention time of compound 46i-1: 6.576 min (the absolute configuration had not been deteunined, and its structure was one of the above faimulas 46i-a and 46i-b);
Retention time of compound 46i-2: 8.951 min (the absolute configuration had not been determined, and its structure was one of the above formulas 46i-a and 46i-b, as well as it was an isomer of compound 46i-1, namely, when the structure of compound 46i-1 was the structure of formula 46i-a, the structure of compound 46i-2 was the structure of formula 46i-b; when the structure of compound 46i-1 was the structure of formula 46i-b, the structure of compound 46i-2 was the structure of formula 46i-a).
Step 10:
trans-1 -(3'-fluoro-[ I ,4'-bipiperidinj-4-y1)-3 -(4-phcnoxyphcnyI)-1H-pyrazolo [3 ,4-dlpyrimi din-4-amine-P1 (46j) Trans-tert-butyl 4-[444-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-y11-1-piperidy11-3-fluoro-piperidine-l-carboxylate-P I (46i-1, its structure was one of formula 46i-a and formula 46i-b) (420 mg, 0.71 mmol) was dissolved in 20 mL
of DCM, and 8 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was dissolved with 30 mL of 5 mol/L NaOH
solution, and extracted with DCM (30 mL x 4). The organic phase was combined, washed with I mol/L NaOH solution (30 mL x 2), dried over anhydrous sodium sulphate, and concentrated under reduced pressure, to obtain trans-1-(3'-fluoro-[1,41-bipiperidin]-4-y1)-3-(4-phenoxypheny1)-1H -pyrazo lo [3,4-d] pyrimidin-4-amine-(46j) (340 mg, yield: 98%), and the configuration of the chiral carbon thereof was consistent with that of the corresponding chiral carbon of the raw material (compound 46i-1) in the tenth step.
1H NMR (400 MHz, CDC13) 6 8.36 (s, 111), 7.71 -7.61 (m, 2H), 7.43 -7.33 (m, 211), 7.20- 7.11 (m, 3H), 7.11 -7.04 (m, 2H), 5.52 (br.s, 2H), 4.84 - 4.72 (m, 1H), 4.71 - 4.46 (m, 1H), 3.43 -3.33 (m, 1H), 3.17 - 2.99 (m, 3H), 2.86 -2.75 (m, 1H), 2.74- 2.50 (m, 4H), 2.49 -2.31 (m, 2H), 2.11 - 1.97 (m, 211), 1.94 - 1.84 (m, 114), 1.84- 1.70 (m, 1H), 1.62- 1.48 (m, 1H).
Date Recue/Date Received 2021-09-09 LCMS miz = 488.3 [M+ 1] .
Step 11:
trans-tert-butyl 3 -(4-(4-amino-3 -(4-plienoxyphenyl)- 1H-pyrazolo [3 ,4-d jpyrimidin- I -y1)-31-fluoro41 ,4'-bi pi peridin ]-1`-yl)azetidine- I -carboxylate-P 1 (46k) Trans-1-(3`-fluoro-[1,4'-bipiperidin]-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-am ine-P1 (46j) (300 mg, 0.62 turnol) was dissolved in 30 mL of DCE, and tert-butyl 3-oxoazetidine- 1 -carboxylate (211 mg, 1.23 mmol) was added, the mixture was stirred at room temperature for 10 min, then sodium triacetoxyborohydride (522 mg, 2.46 mmol) was added, and the mixture was stirred at room temperature for 16 h. The reaction solution was extracted with DCM (30 mL
x 3), and the organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethancimethanol (v/v) = 20 : 1), to obtain trans-tert-butyl 3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-l-y1)-3'-fluoro41,4'-bipiperidin]-11-ypazetidine- 1 -carboxylate-P1 (46k) (380 mg, yield: 95%), and the configuration of the chiral carbon thereof was consistent with that of the corresponding chiral carbon of the raw material (compound 46i-1) in the tenth step.
LCMS m/z = 643.4 [M+1]+.
Step 12:
trans-1-(1'-(azetidin-3-y1)-3'-fluoro- [1,4'-bipi peridin]-4-y1)-3-(4-phenoxypheny1)-1H-py razo lo[3,4-d] pyrim id in-4-am in e-Pl (461) Trans-tert-butyl 3-(4-(4-amino-3 -(4-phenoxypheny1)-1H-pyrazolo [3 ,4-d]pyrimidin-1 -y1)-3 '-fluoro41 ,4'-bipiperidinj-11-yl)azetidine-1-carboxyl ate-P1 (46k) (380 mg, 0.59 mmol) was dissolved in 20 mL of DCM, and 8 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 h. The reaction system was directly concentrated under reduced pressure, and the residue was dissolved with 30 mL of 5 mol/L NaOH solution, and extracted with DCM (30 mL x 4). The organic phase was combined, washed with 1 mol/L NaOH solution (30 mL x 2), dried over anhydrous sodium sulphate, and concentrated under reduced pressure, to obtain the crude product trans-1-(1 '-(azetidin-3- y1)-3'-fluoro-[1,4'-bip iperid in]-4-Date Recue/Date Received 2021-09-09 y1)-3-(4-phenoxypheny1)-11-I-pyrazolo[3,4-d]pyrimidin-4-amine-P1 (461) (260 mg), and the configuration of the chiral carbon thereof was consistent with that of the corresponding chiral carbon of the raw material (compound 46i-1) in the tenth step.
LCMS m/z = 543.3 [M+1,1 .
Step 13:
trans-5-(3-(4-(4-amino-3-(4-phenoxyplienyl)- I H-pyrazolo[3,4-d]pyrimidin-1-y1)-3'-fluoro-[1,4'-bipiperidin]-1i-ypazetidin-1-y1)-2-(2,6-dioxopiperidin-3-y1)isoindoline-1,3-dione-P1 (compound 46-1) N
0 = N
F
41, No 0 N

formula 46-a or H2N , N
\N 0 0 NH

formula 46-b The above crude product trans-1-(1'-(azetidin-3-y1)-3'-fluoro-[1,4'-bipiperidini-s 4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine-P1 (461) (260 mg) was dissolved in 15 mL of DMSO, and 1.5 mL of D1PEA and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (191 mg, 0.69 mmol) were added, the reaction was stirred at SO C for 5 h. The Date Recue/Date Received 2021-09-09 reaction solution was cooled to room temperature, quenched by adding 30 mL of water, and extracted with 100 mL of ethyl acetate. The organic phase was washed with 100 inL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 15 : 1), to obtain trans-5-(3 -(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazo lo [3 ,4-d]pyrim icli n-l-y1)-3t-fluoro-[1,4'-bip iperidin]-1'-yl)azetidin- 1-y1)-2-(2,6-dioxopiperidin-3 -yflisoindoline-1,3-dione-P I (compound 46-1) (220 mg, two-step yield calculated from compound 46k: 47%). The structure of compound 46-1 was one of the structures shown in 46-a and 46-b above, and the configuration of the chiral carbon thereof was consistent with that of the corresponding chiral carbon of the raw material (compound 46i-1) in the tenth step.
'H NMR (400 MHz, CDC13) 8 9.28 (s, 1H), 8.39 (s, 1H), 7.69 - 7.60 (m, 3H), 7.42 -7.34 (m, 2H), 7.20- 7.11 (m, 3H), 7.10- 7.04 (m, 2H), 6.79 (d, 1H), 6.53 (cid, 1H), 5.71 (br.s, 2H), 4.93 (dd, 1H), 4.87 -4.60 (m, 2H), 4.14 -4.07 (m, 2H), 3.90 -3.81 (m, 2H), 3.50 - 3.40 (in, 1H), 3.24 -2.98 (m, 3H), 2.94 -2.62 (in, 7H), 2.50 -2.33 (in, 2H), 2.17- 1.94 (in, 6H), 1.70- 1.60 (m, 1H).
LCMS miz ¨ 799.3 [M+1]+.
Example 46-2:
trans-5-(3-(4 -(4-amino-3-(4-phenoxypheny1)-1H -pyrazo lo [3 ,4-cl]pyrimidin-1-y1)-3'- fluo ro -[ 1,41-b ipiperid in] - l'-yl)azetid in - 1 -y1)-2 -(2,6-d ioxopi perid in-3 -yl)isoindoline-1,3-dione-P2 (compound 46-2) N
0 \ r F

NH
or Date Recue/Date Received 2021-09-09 N, 0 \ / N-N.,..0 ite 0 NH
N¨Z- 0 F . N...., 0 t H2N \
\ /N
_ ,...-- __,N, _CN . arans)N¨Boc N Step 1 Sep 2 _].._ 0....N,Th _,,...
.--'---N--(trFang) N=.---./
46i2 46m -,,,,NH
\ / N N, H2N - \
0 a (trans) I
0 \ _4s1 N ------Th F
v..
46n N .., (trans) 460 ,soc \--NH
H2N- N\
\ / N
F
Step 4 Formula 46-b or NH
H2N \ f \N " -IC
0 __ 0-C, N
Formula 46-a 1 ......,......- N_ \>\-Ntil 0 Compound 46-2 0 Step 1:
trans-1-(3'-fluoro- ll ,4'-bipiperi di n1-4-y1)-3-(4-ph enoxypli enyl)- I H-s pyrazolo[3,4-d]pyrimidin-4-amine-P2 (46m) Trans-tert-butyl 44444-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-y1]-1 -piperidyl] -3-fluoro-piperidine-1-carboxylate-P2 (46i-2, an isomer of compound 46i-1 in example 46-1) (420 m2., 0.71 mmol) was dissolved in 20 m1_, of Date Recue/Date Received 2021-09-09 DCM, and 8 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 h. Upon completion of the reaction, the system was directly concentrated under reduced pressure, and the residue was dissolved with 30 inL
of 5 mol/L NaOH solution, and extracted with DCM (30 mL x 4). The organic phase was combined, washed with I mol/L NaOH solution (30 mL x 2), dried over anhydrous sodium sulphate, and concentrated under reduced pressure, to obtain trans-1-(3'-fluorot 1,4'-bipiperidin]-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-dlpyrimidin-4-amine-P2 (46m) (330 mg, yield: 95%), and the configuration of the chiral carbon thereof was consistent with that of the corresponding chiral carbon of (compound 46i-2).
1H NMR (400 MHz, CDC13) 6 8.36 (s, 1H), 7.70- 7.61 (in, 2H), 7.43 -7.34 (m, 211), 7.20 - 7.11 (m, 3H), 7.10 - 7.05 (in, 2H), 5.54 (brs, 211), 4.85 -4.72 (m, 114), 4.68 -4.46 (in, 1H), 3.43 -3.33 (m, 1H), 3.17 - 2.99 (m, 3H), 2.86 -2.75 (m, 1H), 2.74 - 2.50 (in, 4H), 2.48 - 2.31 (in, 2H), 2.10- 1.96 (m, 211), 1.93 - 1.81 (m, 1H), 1.79- 1.62 (in, 1H), 1.61 - 1.46 (m, 111).
LCMS m/z = 488.3 [M-i- 1 ]4'.
Step 2:
trans-tert-butyl 3 -(4-(4-amino-3 -(4-phenoxypheny1)-1H-pyrazo lo [3 ,4-d]pyrimidin-1 -yI)-3 '-fluoro41 ,4'-bipiperidin]-1`-ypazetidine-1 -carboxylate-P2 (46n) Trans- I -(3`-fluoro-[1,4'-bipiperidin]-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-am ine-P2 (46m) (300 mg, 0.62 mmol) was dissolved in mL of DCE, and tert-butyl 3-oxuazetidine- 1 -carboxylate (211 mg, 1.23 mmol) was added, the mixture was stirred at room temperature for 10 min, then sodium triacetoxyborohydride (522 mg, 2.46 mmol) was added, and the mixture was stirred 25 at room temperature for 16 h. The reaction solution was extracted with DCM (30 niL
x 3), and the organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20 : 1), to obtain trans-tert-butyl 3-(4-(4-amino-30 3-(4-phenoxypheny1)-11-1-pyrazolo[3,4-d]pyrimidin- I -y1)-3'-fluoro-[1,4'-bipiperidin]-1'-ypazetidine- 1 -carboxylate-P2 (46n) (390 mg, yield: 98%), and the Date Recue/Date Received 2021-09-09 configuration of the chiral carbon thereof was consistent with that of the corresponding chiral carbon of (compound 46i-2).
LCMS in/z ¨ 643.4 [M-Flr.
Step 3:
trans-1-(1'-(azetidin-3-y1)-3'-fluoro-[ I ,4'-bipiperidin]-4-y1)-3-(4-phenoxypheny1)-1H-pyrazol o[3,4-d] py timid in- 4-am in e-P2 (46o) Trans-tert-butyl 3-(4-(4-amino-3-(4-phenoxypheriy1)- I H-pyrazolo [3 ,4-d]pyrimidin- 1-y1)-3 '-fluoro41 ,4'-bipiperidinj- 1'-yl)azetidine-1-carboxylate-P2 (46n) (370 mg, 0.58 mmol) was dissolved in 20 mL of DCM, and 8 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 h. The reaction system was directly concentrated under reduced pressure, and the residue was dissolved with 30 rnL of 5 mol/L NaOH solution, and extracted with DCM (30 ail x 4). The organic phase was combined, washed with 1 mol/L NaOH solution (30 mL x 2), dried over anhydrous sodium sulphate, and concentrated under reduced pressure, to obtain the crude product trans-1-(1'-(azetidin-3-y1)-3'-fluoro-[1,4'-bipiperidin]-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine-P2 (46o) (270 mg), and the configuration of the chiral carbon thereof was consistent with that of the corresponding chiral carbon of (compound 46i-2).
LCMS m/z = 543.3 [M+1]+.
Step 4:
trans-5-(3-(4-(4-am ino-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-d]pyri mid in-1-y1)-3'-fluoro-[ 1,4'-bipiperidin] - I '-y Dazetidin-l-y yl)isoindoline-1,3-dione-P2 (compound 46-2) N
=0 \ = N
N F

N

formula 46-b Date Recue/Date Received 2021-09-09 or 0 = _NI
N
=

N

formula 46-a The above crude product trans-1-(1'-(azetidin-3-y1)-3'-fiuoro-11,4T-bipiperidini-s 4-y1)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine-P2 (46o) (270 mg) was dissolved in 15 mL of DMSO, and 1.5 mL of DIPEA and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (191 mg, 0.69 mmol) were added, the reaction was stirred at 80 C for 5 h. The reaction solution was cooled to room temperature, added 30 mL of water, and extracted with 100 mL of ethyl acetate. The organic phase was washed with 100 mL
of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 15 1), to obtain trans-5-(3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazo I o [3 ,4-d]pyrimidin-1-y1)-3`-fluoro41,4'-bipiperidin]-1 '-yl)azetidin-l-y1)-2-(2,6-dioxopiperidin-3-y Disoindol ine-1,3-dione-P2 (compound 46-2) (260 mg, two-step yield calculated fi-om compound 46n:
56%).
The structure of compound 46-2 was one of the structures shown in 46-b and 46-a above, and the configuration of the chiral carbon thereof was consistent with that of the corresponding chiral carbon of the raw material (compound 46i-2) in the first step;
namely, compound 46-2 was an isomer of compound 46-1 in example 46-1.
1H NMR (400 MHz, CDCI3) 6 8.86 (s, 1H), 8.38 (s, 111), 7.69 - 7.60 (m, 3H), 7.43- 7.34 (m, 2H), 7.21 - 7.11 (m, 311), 7.10- 7.04 (m, 211), 6.79 (d, 111), 6.53 (dd, 111), 5.63 (brs, 2H), 4.93 (dd, 11-1), 4.87 - 4.59 (m, 2H), 4.14 - 4.07 (m, 2H), 3.90 -3.81 (in, 2H), 3.50 - 3.40 (in, 111), 3.25 - 3.00 (in, 3H), 2.94 - 2.62 (in, 7H), 2.51 -Date Recue/Date Received 2021-09-09 2.35 (m, 211), 2.18 - 1.94 (m, 611), 1.77 - 1.62 (m, 1H).
LCMS in/z = 799.3 [M4-1]+.
Example 47:
(7S)-7-(1-(1-(2-(2,6-dioxopiperidin-3-y1)-1,3-dioxo-isoindolin-5-yl)azetidin-3-y 1)p (4-phenoxypheny1)-4,5,6,7-tetrahydropyrazo lo [1,5-a]py rimidine-3-carboxami de (compound 47) =0 HN
r Step !
N
HN N FIN' /
L4;
311, Compound 47 '13 (7S)-741-(azetidin-3-y1)-4-piperidy1}-2-(4-phenoxypheny1)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (3 lb) (250 mg, 0.53 mmol) was dissolved in 25 mL of DMSO, and 1.0 mL of DIPEA and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (220 mg, 0.80 mmol) were added, the reaction was stin-edat at 80 C for 5 h.
The reaction solution was cooled to room temperature, added 50 mL of water, and extracted with 100 mL of ethyl acetate. The organic phase was washed with 100 mL
of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 15 : 1), to obtain (7S)-7-( I
-(1-(2-(2,6-dioxopiperidin-3-y1)-1,3-dioxo-isoindo Date Recue/Date Received 2021-09-09 2-(4-phenoxypheny1)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (compound 47) (210 mg, yield: 54%).
1H NMR (400 MHz, CDC13) 6 8.53 - 8.41 (in, 1H), 7.63 (d, 1H), 7.53 - 7.46 (m, 2H), 7.40- 7.32 (m, 2H), 7. l 8 - 7.11 (m, 1H), 7.10- 7.01 (m, 4H), 6.78 (d, 1H), 6.63 - 6.57 (m, I H), 6.52 (dd, 1H), 5.21 (br.s, 2H), 4.95 - 4.87 (m, 1H), 4.14 -4.05 (m, 2H), 3.98 - 3.78 (in, 2H), 3.47 - 3.29 (m, 3H), 3.06 - 2.64 (iii, 5H), 2.35 -2.05 (in, 4H), 2.02 - 1.86 (m, 2H), 1.86- 1.76 (m, 1H), 1.74 - 1.38 (m, 41-1).
LCMS m/z = 729.3 [M+1] .
Example 48:
(7S)-7-( I '-(2-(2,6-dioxopiperidin-3-y1)-1,3-dioxo-isoindolin-5-y1)-{1,4'-bipiperidin]-4-y1)-2-(4-phenoxyphenyl )-4,5,6,7-tetrahydropyrazolo [1 õ5-a]pyrimidin c-3-carboxamide (compound 48) 11, 0 HN

===-,- 9 H 0 0 U1' Step I
*N
H,N J 1 HN) I-114 -30.c Compound (7S)-2-(4-phenoxypheny1)-7-[ I -(4-piperidy1)-4-piperidy1]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-earboxamide (30e) (250 mg, 0.50 mmol) was dissolved in 25 mL of DMSO, and 1.0 mL of DIPEA and 2-(2õ6-dioxopipericlin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (207 mg, 0.75 mmol) were added, the reaction was stirredat at 80 C for 5 h.
The reaction solution was cooled to room temperature, added 50 inL of water, and Date Recue/Date Received 2021-09-09 extracted with 100 mL of ethyl acetate. The organic phase was washed with 100 mL
of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 15 : 1), to obtain (7S)-7-(1'-(2-(2,6-dioxopiperidin-3-y1)-1,3-dioxo-isoindolin-5-y1)41,4'-bipiperidinj-4-y1)-2-(4-phenoxypheny1)-4,5,6,74etrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (compound 48) (200 mg, yield: 53%).
'1-1 NMR (400 MHz, CDC13) 6 8.81 (br.s, 1H), 7.66(d, 1H), 7.53 - 7.45 (m, 2H), 7.40- 7.32 (m, 211), 7.29 -7.24 (m, 111), 7.19- 7.10 (m, 111), 7.10 -6.99 (m, 511), 6.62 - 6.57 (m, 1H), 5.26 (br.s, 2H), 4.97- 4.88 (m, 1H), 4.16- 4.06 (m, 1H), 4.04 -3.94 (m, 2H), 3.46 - 3.36 (m, 2H), 3.21 - 3.03 (m, 2H), 3.03 -2.91 (m, 2H), 2.90 -2.65 (m, 4H), 2.47 - 2.22 (m, 3H), 2.22 -2.02 (in, 5H), 1.87- 1.58 (m, 6H).
LCMS m/z = 757.3 [M-F-Example 49-1 cis-5-(3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazol o [3,4-d]pyri mi din-l-yI)-3'-fluoro-[1,41-bipiperidin]-1'-y1 )azetidin-l-y1)-2-(2,6-dioxopiperid in-3 -ypisoindoline-1,3-dione-P1 (compound 49-1) NH

N-or \N-N¨CAN, NH

N
Date Recue/Date Received 2021-09-09 ...c) Q
NBoc Boo a 18a --(C1:14.
/ N
N-/
110 F , 18a-1 ond 18a-2 NBoc N_ , o . , NNI IQ_ H2N \ 7N H2.. m \ , N
Sp 3 slop 2 H2N¨HN 1 0 ' N.y^-1 F __ N' 1 0 \NI-N"-CkLIF
N=4 1._____,NTel a 49a NH 49b 18a-1 o Boo N-.,-\
H2N \ ,N
Slep4 Step 5 ______________ . __________________________ .
a 49c \,-NH
H2 \ iN
N F
0 0 Or L N c_IN

Compound 49-1 Step 1:
cis-tert-butyl 4-(4-amino-3-(4-phenoxypheny1)- 1H-pyrazolo[3,4-d]pyrimidin-1 -y1)-31-fluoro-[ 1 ,4r-bi piperidinej- 1 '-earboxylate-P1 (1 8a-1) and cis-tert-butyl 4-(41-amino-3-(4-ph enoxyph eny1)- 1 H-pyrazolo[3,41-d]pyrim i din-1 -y1)-3'-fluoro-[ 1 ,4'-bipiperi dine]- 1 '-carboxylate-P2 (1 8a-2) __GN JNRoc N, H2N / \N
N=7, and formula 18a-a Date Recue/Date Received 2021-09-09 O
CNBoc N, N
H2N \N
formula 18a-b Compounds Iga.-1 and 18a-2 were separated and prepared from compound 18a by means of high performance liquid chromatography. The preparation conditions were as follows:
instrument and preparative column: using MG II preparative SFC (SFC-1) to prepare the liquid phase, preparative column model: Cellulose-2, 250 x 30 mm I.D., 5 um, Preparation method: the crude product was dissolved with methanol/dichloromethane, to prepare into a sample solution.
Mobile phase system: sCO2/ ethanol (containing 0.1% ammonia water), isocratic elution: sCO2/ethanol (containing 0.1% ammonia water) = 60/40.
Flow rate: 50 mL/min Analysis method for compounds 18a-1 and 18a-2:
is Instrument: Waters UPC2 analytical SFC (SFC-H) Chromatographic column: Cellulose-2, I.D.
Specification: 150 mm x 4.6 mm, 3 um Mobile phase A: sCO2 Mobile phase B: ethanol (containing 0.05% diethylamine) Column temperature: 35 C
Flow rate: 2.5 mL/min Wavelength: 220 nm Isocratic elution: mobile phase A: B 60 : 40.
Retention time of compound 18a-1: 7.201 min; the absolute configuration had not been determined, and its structure was one of the above formulas 18a-a and 18a-b;
'H NMR (400 MHz, CDC13) 6 8.29 (s, 1H), 7.58 (d, 1H), 7.35 - 7.27 (m, 2H), Date Recue/Date Received 2021-09-09 7.23 - 7.16 (m, 1H), 7.13 - 7.04 (m, 314), 7.03 -6.97 (m, 211), 5.51 (br.s, 2H), 4.99 -4.62 (m, 214), 4.46 - 4.10 (m, 2H), 3.14 - 2.94 (m, 214), 2.87 - 2.25 (m, 714), 2.01 -1.86 (m, 3H), 1.65 - 1.57 (in, I H), 1.39 (s, 9H).
Retention time of compound 18a-2: 8.585 min. the absolute configuration had not been determined, and its structure was one of the above formulas 18a-a and 18a-b, as well as it was an isomer of compound 18a-1, namely, when the structure of compound 18a-I was the structure of fonnula 18a-a, the structure of compound 18a-2 was the structure of formula 18a-b; when the structure of compound 18a-1 was the structure of formula 18a-b, the structure of compound 18a-2 was the structure of formula 18a-a.
11-1 NMR (400 MHz, CDC13) 6 8.29 (s, 1H), 7.58 (d, 1H), 7.35 - 7.27 (m, 2H), 7.21 - 7.16 (in, 1H), 7.13 - 7.04 (m, 3H), 7.03 - 6.97 (n, 21-1), 5.41 (br.s, 2H), 5.00 -4.60 (m, 2H), 4.53 - 4.03 (m, 2H), 3.15 - 3.00 (m, 2H), 2.92 - 2.22 (m, 7H), 2.02 -1.85 (m, 314), 1.69- 1.51 (in, 1H), 1.39 (s, 9H).
Step 2:
cis-143 '-fl uoro-[1,4`-bi piperidin]-4-y1)-3-(4- phenoxypheny1)-1 H-pyrazo lo [3,4-d]pyrimidin-4-amine-P1 (49a) Cis-tert-butyl 4-(4-amino-3 -(4-phenoxypheny1)-114-pyrazolo [3 ,4-d]pyrimidin-1-y1)-31-fluoro-[1,4'-bipiperidine]-1'-carboxylate-P1 (18a-1, its structure was one of formula 18a-a and formula 18a-b) (1.0 g, 1.7 mmol) was dissolved in 20 mL of DCM, and 5 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 3 h. To the reaction solution was slowly added dropwise 30 mL
of saturated sodium bicarbonate solution, and 30 mL of dichloromethane and 50 mL
of water were added. The organic phase was separated, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, to obtain the crude product cis-1-(3`-fluoro-[1,4'-bi pi peri d in -4-yI)-3-(4-ph enoxyph enyI)-1H -pyrazo lo [3,4-d]pyrimidin -4 -am ine-P1 (49a) (0.8 g), and the configuration of the chiral carbon thereof was consistent with that of the corresponding chiral carbon of (compound 18a-1).
LC-MS m/z = 488.3 [114+1].
Step 3:
Date Recue/Date Received 2021-09-09 Cis-tert-butyl 3 -(4-(4-amino-3 -(4 -phenoxypheny1)-111 -pyrazolo [3 ,4-d]pyrim idin-l-y1)-3 -fluoro-[1 ,4'-bipiperidin]-l'-y1)azetidine-1-earboxylate-P1 (49b) The above crude product cis-1-(3'-fluoro-[1,4'-bipiperidin]-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-d jpyrimidin-4-amine-P1 (49a) (0.8 g) was dissolved in 30 mL of DCE, and tert-butyl 3-oxazetidine- 1 -carboxylate (0.6 g, 3.5 mmol) was added, the mixture was stirred at room temperature for 10 min, then sodium triacetoxyborohydride (0.7 g, 3.3 mmol) was added, and the reaction was stirred at room temperature for 16 h. To the reaction solution was added 30 rtiL of saturated sodium bicarbonate solution, and 50 mL of dichloromethane and 50 mL
of water were added. The organic phase was separated, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (diehloromethane/methanol (v/v) = 20 : 1), to obtain cis-tert-butyl 3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-l-y1)-3'-fluoro-[ I ,4'-bip ip erid inj-1 '-yl)azetidine- 1 -carboxylate-Pl (49b) (1.0 2, two-step yield calculated from compound 18a-1: 92%), and the configuration of the chiral carbon thereof was consistent with that of the corresponding chiral carbon of (compound 18a-1).
LC-MS m/z ¨ 643.4 [M+1r.
Step 4:
Cis-1 -(1'-(azetidin-3-y1)-3'-fluoro-[1,4T-bipiperidin]-4-y1)-3-(4-phenoxypheny1)-1H-pyrazo lo[3 ,4-dipyrimidin -4-am in e-P1 (49c) Cis-tert-butyl 3-(4-(4-arnino-3-(4-plienoxyplieny1)-1H -pyrazo lo [3,4-d[pyrimidin-l-y1)-31-fluoro-[1 ,4'-bipiperidin]- lt-ypazetidine-1-carboxylate-P I (49b) (1.0 g, 1.56 mmol) was dissolved in 20 mL of DCM, and 5 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 3 h. To the reaction solution was slowly added dropwise 30 mL of saturated sodium bicarbonate solution, and 30 mL of dichloromethane and 50 mL of water were added. The organic phase was separated, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, to obtain the crude product cis-1-(1'-(azetidin-3-y1)-3'-fluoro-[1,4'-bipiperidin]-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo [3 ,4-d]pyrimidin-4-amine-(49c) (0.7 g), and the configuration of the chiral carbon thereof was consistent with Date Recue/Date Received 2021-09-09 that of the corresponding chiral carbon of (compound 18a-1).
LCMS m/z = 543.3 [M-4-1]+.
Step 5:
cis-5-(3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo13,4-d jpyri mi din-1 -y1)-3'-fl uoro-[1,4'-bi piperi din] -1'-yl)azetidin-l-y1)-2-(2,6-dioxopi perid in-soi tido] ne-1,3-dione-P1 (compound 49-1) --ON AN NH

formula 49-a or /N

NH

formula 49-b The above crude product cis-1-(1'-(azetidin-3-y1)-3'-fluoro-[1,4'-bipiperidin1-y1)-3-(4-phenoxypheny1)-1H-pyrazo1o[3,4-d]pyrimidin-4-amine-P1 (49e) (0.2 g) was dissolved in 5 mL of DMSO, and DIPEA (0.21 g, 1.6 mmol) and 242,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (0.14 g, 0.5 mmol) were added, the reaction was stirred at 90 C for 3 h. The reaction solution was cooled to room temperature, and 50 mL of ethyl acetate and 50 rriL of water were added. The organic phase was separated, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) ¨ 20 : 1), to obtain cis-5-(3-(4-(4-arnino-3-(4-phenoxyphenyI)-1H-pyrazolo[3 ,4-d]pyrimidin-1-y1)-3'-fluoro-[1,4'-bipiperidinj-Date Recue/Date Received 2021-09-09 yl)azeti din- 1-yI)-2-(2,6-di oxopiperidin-3-yl)isoindoline-1,3-dione-P1 (compound 49-1) (0.05 g, two-step yield calculated from compound 49b: 14%). The structure of compound 49-1 was one of the structures shown in 49-a and 49-b above, and the configuration of the chiral carbon thereof was consistent with that of the corresponding chiral carbon of the raw material (compound 18a-1) in the second step.
11-1 NMR (400 MHz, CDC13) 6 8.97 (s, 1H), 8.38 (s, 1H), 7.69 - 7.59 (m, 3H), 7.43 - 7.34 (m, 2H), 7.20 - 7.04 (m, 5H), 6.78 (d, 1H), 6.52 (dd, 1H), 5.69 (hrs, 2H), 5.13 - 4.88 (in, 2H), 4.84 -4.73 (m, 1H), 4.15 - 4.05 (m, 21-1), 3.99 - 3.87 (in, 21-1), 3.52 - 3.43 (in, 111), 3.28 - 3.12 (m, 311), 3.09 - 3.00 (m, 111), 2.93 - 2.33 (in, 811), 2.24 - 2.00 (m, 6H), 1.84- 1.76 (m, 1H).
LCMS in/z = 799.3 [M+1]
Example 49-2 cis-5-(3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-d]pyrimidin-l-y1)-3'-flii oro-[1,4'-bi piperi din] -1'-yl)azetid n-1-y1)-2-(2,6-d ioxopi perid in-3 -ypisoindoline-1,3-dione-P2 (compound 49-2) /N

or H2N--tz/N

NH

Date Recue/Date Received 2021-09-09 1,4 m 14'1 H2N /N
Sp 2 Sup 18a-2 ___________ o 'NA
0 ".1 =
49d cis). , NH 49e (cis)N
Boc H2N-Ar_p swp -I
F ________ p-0 c?µ/---( o49f \--NH
1-12N \ /NI
0 or 0 = F

o Compound 49-2 Step 1:
cis- 1-(31-fluoro41,4'-bipiperidi n]-4-y1)-3-(4-phenoxypheny1)- 111-py razo lo [3,4-dipyrimidin-4-amine-P2 (49d) Cis-tert-butyl 4-(4-ami no-3-(4-ph enoxypheny1)-1H -pyrazol o [3 ,4-d] pyri midi n-1-y1)-3'-fluoro-[1,4'-bipiperidine]-1'-carboxylate-P2 (18a-2, its structure was one of formula 18a-a and formula 18a-b, an isomer of compound 18a-1) (0.82 g, 1.4 mmol) was dissolved in 20 rnL of DCM, and .5 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 3 h. To the reaction solution was slowly added dropwise 30 mL of saturated sodium bicarbonate solution, and 30 mL of dichloromethane and 50 mL of water were added. The organic phase was separated, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, to obtain the crude product cis-143 `-fluoro-[1,4'-bipiperidini-4-y1)-3 -(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-aminc-P2 (49d) (0.62 g), and the configuration of the chiral carbon thereof was consistent with that of the corresponding chiral carbon of compound 18a-2.
LC-MS m/z = 488.3 [M+1r.
Step 2:
Cis-tert-butyl 34444- amino-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-Date Recue/Date Received 2021-09-09 d]pyrimidin-l-y1)-3'-fluoro-[1,4'-bipiperidin]-1'-yDazetidine-1-carboxylate-P2 (49e) The above crude product cis-1-(3'-fluoro-[1,4'-bipiperidini-4-y1)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-arnine-P2 (49d) (0.62 g) was dissolved in 30 mL of DCE, and tert-butyl 3-oxazetidine-1-carboxylate (0.43 g, 2.5 MM01) was added, the mixture was stirred at room temperature for 10 min, then sodium triacetoxyborohydride (0.64 g, 3.0 mmol) was added, and the reaction was stirred at room temperature for 16 h. To the reaction solution was added 30 mL
of saturated sodium bicarbonate solution, and 50 triL of dichloromethane and 50 mL of water were added. The organic phase was separated, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20 : 1), to obtain cis-tert-butyl 3-(4-(4-amino-3-(4-phenoxypheny1)- 1H-pyrazolo [3 ,4-d]pyrimidin- 1-y1)-3'-fluoro- [1,4'-biniperidinl-1 '-ypazetidine-1-carboxylate-P2 (49e) (0.6 g, two-step yield calculated from compound 18a-2: 67%), and the configuration of the chiral carbon thereof was consistent with that of the corresponding chiral carbon of compound 18a-2.
LC-MS m/z ,----- 643.4 [M+ I ].
Step 3:
Cis-1 -(1 '- (azetidin-3-y1)-3'-fluoro-[1,4'-bipiperidin]-4 -yI)-3-(4-phenoxypheny1)- I H-pyrazolo[3,4-d]pyrimidin-4-amine-P2 (490 Cis-tert-butyl 3-(4-(4- ami no-3-(4-phenoxyphen y1)-1H-pyrazo lo [3,4-d]pyrimidin- 1-y1)-3'-fl uoro-[1,4'-bipiperidin]-lf-yl)azetidine-1-carboxyl ate-P2 (49e) (0.6 g, 0.93 mmol) was dissolved in 20 mL of DCM, and 5 rnL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 3 h. To the reaction solution was slowly added dropwise 30 inL of saturated sodium bicarbonate solution, and 30 mL of dichloromethane and 50 mL of water were added. The organic phase was separated, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, to obtain the crude product cis-1-(1'-(azetidin-3-y1)-3'-fluoro-[1,4t-bipiperidin]-4-y1)-3-(4-phenoxyphenyI)-1H-pyrazolo [3 ,4-dipyrimidin-4-amine-(490 (0.45 g), and the configuration of the chiral carbon thereof was consistent with that of the corresponding chiral carbon of compound 18a-2.
Date Recue/Date Received 2021-09-09 LCMS m/z =543.3 [M+I]1 Step 4:
cis-5-(3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo43,4-d]pyrimidin-l-y1)-3'-fluoro-[1,4'-bipiperidin )azetidin- I -y1)-2-(2,6-dioxopiperidin-3-s yl)isoi ndoline-1,3-dione-P2 (compound 49-2) N
F

formula 49-b or N.
H2N¨ N

=

NH

formula 49-a The above crude product cis-1-(1'-(azetidin-3-y1)-3'-fluoro-[1,4'-bipiperidin]-y1)-3-(4-phenoxypheny1)-111-pyrazolo[3,4-d]pyri.midin-4-amine-P2(49f) (0.2 g) was dissolved in 5 mL of DMSO, and DIPEA (0.21 g, 1.6 mmol) and 242,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (0.14 g, 0.5 mmol) were added, the reaction was stirred at 90 C for 3 h. The reaction solution was cooled to room temperature, and 50 mL of ethyl acetate and 50 mL of water were added. The organic phase was separated, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20 : 1), to obtain cis-5-(3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo [3 ,4-dipyrimidin-1-y1)-3'-fluoro-[1,4'-bipiperidin 1'-yl)azeti din- 1-y1)-2-(2,6-di oxopiperidi n-3-yl)iso indoline-1,3-dione-P2 (compound Date Recue/Date Received 2021-09-09 49-2) (0.27 g, two-step yield calculated from compound 49e: 82%). The structure of compound 49-2 was one of the structures shown in 49-a and 49-b above, and the configuration of the chiral carbon thereof was consistent with that of the corresponding chiral carbon of the raw material (compound 18a-2) in the first step, namely, compound 49-2 was an isomer of compound 49-1.
11-1 NMR (400 MHz, CDC13) 6 9.66 (s, 1H), 8.38 (s, 1H), 7.67 - 7.60 (m, 3H), 7.42 - 7.34 (m, 2H), 7.20 - 7.11 (m, 3H), 7.10 - 7.04 (m, 2H), 6.78 (d, 1H), 6.52 (dd, 11-1), 5.79 (brs, 2H), 5.13 - 4.88 (m, 2H), 4.83 - 4.72 (m, 1H), 4.16 - 4.04 (m, 214), 4.00 - 3.86 (m, 211), 3.52 - 3.42 (m, 111), 3.24 - 3.12 (m, 311), 3.09 - 3.00 (m, 111), 2.91 - 2.32 (m, 8H), 2.23 - 1.98 (m, 6H), 1.84 - 1.76 (m, I H).
LCMS m/z = 799.4 [M+1]'.
Example 50:
5-(3 -(2-(4-(4-amino-3 -(4-phenoxypheny1)- 1H-pyrazolo[3 ,4-d]pyrimidin-1-yl)piperidin-1 -y1)-7-aza spiro [3 .5 ]nonan-7-y1)azetidin-1-y1)-2-(2,6-dioxopiperid in-3-yl)isoindoline-1,3-dione (compound 50) =

Date Recue/Date Received 2021-09-09 Q jr-iN-Boc OçJFt NH Step 1 0 -'"---..Step 2 0--(Th N sIel, 3 H2N)'/ ir4 509 50b Step 4 Step 5 H2N / \N
N=/
50c 50c1 CiN
\ N

N=j Compound 50 Step I:
tert-butyl 2-(4-(4-am ino-3 -(4-ph en oxyph eny1)-1H-pyrazolo [3 ,4-d]pyrimidin- I -y 1 )pi peri din -1-y1)-7-azaspiro[3.5]nonane-7-carboxylate (50a) N.
\ H2N N

3 -(4-phenoxyphen y1)- I -(piperidi n-4-y1)-1H-pyrazo lo [3 ,4-d] pyrim idin-4-am ine (la) (see J Med. ('hem. 2015, 58, 9625-9638 for the synthetic method) (400 mg, 1.04 mmol) was dissolved in 5 mL of DCE, and tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (493 mg, 2.06 mmol), glacial acetic acid (0.15 mL, 2.6 mmol) and 10 anhydrous sodium sulphate (700 mg) were successively added at room temperature, the mixture was stirred for 5 min, then sodium triacetoxyborohydride (655 mg, 3.09 mmol) was added, and the mixture was stirred at room temperature for 16 h. To the reaction solution was added 50 inL of water, the pH of the aqueous phase was adjusted to 10 with 2 mol/L sodium hydroxide aqueous solution, and the resulted is solution was extracted with diehloromethane (30 mL x 3). The organic phase was combined, washed with water (20 mL x 2), dried over anhydrous sodium sulphate, Date Recue/Date Received 2021-09-09 and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) =
10:
1-8 : 1), to obtain tert-butyl 2-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d[pyrim idin-1 -yllp iperidin -1 -y1)-7-azaspirol3 . 51n onan e-7-carboxylate (50a) (600 111g, yield: 95%).
LCMS ni/z ¨ 610.4 [M+1]'.
Step 2:
1-(1-(7-azaspiro[3.5]nonan-2-yl)piperidin-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50b) N
\ N

Tcrt-butyl 2-(4-(4-ami no-3-(4-phenoxyphcny1)-1H-pyrazo lo[3,4-d] pyri midi n-1-yl]piperid in-l-y1)-7-azaspiro[3.5]nonane-7-carboxylate (50a) (600 mg, 0.98 mmol) was dissolved in 4 m 1 of dichloromethane, and 2 ml. of trifluoroacetic acid was added, the reaction was carried out at room temperature for 2 h. The pH of the reaction solution was adjusted to 10 with 2 mol/L sodium hydroxide solution, and the aqueous phase was extracted with dichloromethane (10 mL x 3). The organic phase was combined, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, to obtain the crude product 1-(1-(7-azaspiro[3 .5]nonan-2-yl)piperidin-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo [3,4- d]pyrimidin-4- amine (50b) (458 mg).
LCMS m/z = 510.3 [M+1]t Step 3:
tert-butyl 3 -(2-(4-(4 -am no-3 -(4-pherioxyphenyl )-1H-pyrazolo [3 ,4 d]pyrimidin-I-Apiperid in- 1 -y1)-7-azaspiro[3 .5] nonan-7-y Dazetid ne-l-carboxylate (50c) Date Recue/Date Received 2021-09-09 Boc N
N
\ H2N N
The above crude product 1-(1-(7-azaspiro[3.5]nonan-2-yl)piperidin-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50b) (458 mg) was dissolved in 5 mL of DCE, and 1-Soc-3-azetidinone (308 mg, 1.80 mmol), glacial acetic acid (0.13 mL, 2.25 mmol) and anhydrous sodium sulphate (700 mg) were successively added at room temperature, the mixture was stirred for 30 min, then sodium triacetoxyborohydride (634 mg, 2.99 mmol) was added, and the mixture was stirred at room temperature for 16 h. To the reaction solution was added 50 mL
of water, the pH of the aqueous phase was adjusted to 10 with 2 mol/L sodium hydroxide solution, and the resulted solution was extracted with dichloromethane (30 m1, x 3).
The organic phase was combined, washed with water (20 mL x 2), dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 10: 1-8: 1), to obtain tert-butyl 3-(2-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-djpyrimidin-1-yl)piperidin-1-y1)-7-azaspiro[3.5]nonan-7-ypazetidine- 1 -carboxylate (50c) (501 mg, two-step yield calculated from compound 50a: 77%).
LCMS m/z ¨ 665.4 [M+ 1 ]F.
Step 4:
1-(1-(7-(azetidin-3 -y1)-7-azaspiro [3 .5] nonan-2-yl)piperidin-4-y1)-3 -(4-phenoxypheny1)-1H-pyrazolo [3 ,4-d]pyrimidin-4-amine (50d) N., -` N-/ \ N

I`sf Tert-butyl 3 -(2-(4-(4-amino-3 -(4-phenoxypheny1)-1H-pyrazolo[3 ,4-d jpyrimid in-1 -yl)p iperidi n-l-y1)-7-azaspiro[3 .51nonan-7-yl)azetidi ne-l-carboxylate Date Recue/Date Received 2021-09-09 (50c) (501 mg, 0.75 mmol) was dissolved in 5 mL of dichloromethane, and 2 mL
of trifluoroacetic acid was added, the reaction was carried out at room temperature for 2.5 h. The pH of the reaction solution was adjusted to 10 with 2 mol/L sodium hydroxide solution, and the aqueous phase was extracted with dichloromethane (10 mL x 3). The organic phase was combined, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, to obtain the crude product 1-(1-(7-(azetidin-3-yI)-7-azaspiro[3 .5] nonan-2-yppiperidin-4-y1)-344-pherioxyphenyl)-pyrazolo[3,4-d]pyrimidin-4-amine (50d) (350 mg).
LCMS m/z = 565.4 [M 1].
Step 5:
5-(3 -(2-(4-(4-amino-3 -(4-phenoxypheny1)-1H-pyrazo lo [3 ,4-d]pyrim idin -1-yl)piperidin-1 -y1)-7-azaspiro [3 .5]nonan-7-ypazctidin-1 -y1)-2-(2,6-dioxopiperidin-3-yl) isoindoline-1,3- dione (compound 50) o / .4\

N=7-1 The above crude product 1-(1-(7-(azetidin-3-y1)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3 ,4-d]pyrimidin-4-amine (50d) (192 mg) was dissolved in 5 mL of DMSO, and 2-(2,6-dioxopiperidin-3-y1)-5-11uoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (102 mg, 037 mmol) and diisopropylethylarnine (220 mg, 1.70 mmol) were added at room temperature, the reaction was stirred at 80 C for 4 h. The reaction solution was poured into 20 mL of water, and the aqueous phase was extracted with the mixed solvent of dichloromethane/methanol (v/v) = 10 : 1 (30 mL x 3). The organic phase was combined, washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) =
15:
1-8 :
1), to obtain 5 -(3 -(2-(4-(4-amino-3-(4-phenoxypheny1)-1-pyrazolo [3,4-d]pyrim idin-1 -yl)piperidin-1-y1)-7-azaspiro [3 .5] nonan-7-yl)azetidin-l-y1)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (compound 50) (112 mg, two-step yield Date Recue/Date Received 2021-09-09 calculated from compound 50c: 33%).
11-1NMR (400 MHz, CDC13) 6 8.29 (s, 11-1), 7.61 - 7.52 (m, 3H), 7.36 - 7.28 (m, 2H), 7.16 -.6.97 (m, 5H), 6.70 (d, 1H), 6.44 (dd, 1H), 5.76 (br.s, 21), 4.85 (dd, 1H), 4.80 - 4.66 (m, 1H), 4.06 - 3.96 (m, 2H), 3.86 - 3.76 (m, 2H), 3.28 - 3.18 (m, 1H), 3.07 - 2.96 (m, TH), 2.86 - 2.57 (m, 5H), 2.43 - 2.31 (m, 3H), 2.31 - 2.17 (m, 3H), 2.09 - 1.92 (in, 7H), 1.77 - 1.66 (m, 2H), 1.65 - 1.54 (m, 4H).
LCMS miz = 821.4 [M+1]+.
Example 51:
5-(2'-(4-(4-amino-3-(4-phenoxypherty1)-111-pyrazolo[3,4-d]pyrimidin-1 yl)piperidin-l-y1)-7,T-diaza[2,7`-bispiro[3.5]nonan]-7-y1)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (compound 51) H
N ONO

H2N \
N
N--OCN z 0 Date Recue/Date Received 2021-09-09 N--µ.-- \

_f H2N
N
Step 1 Step 2 .µN-N''('-'1 t..,_ ¨o-0 ", N
N
=

,N
n411 a -.-N "--. 0 6 -----A--MNFI
N.soc \
0 I a 51a 51 b N.--,. N-----NN

\ / N H2 N .=- 17\
¨ =,. Step 4 N-----C:µ,N
__ NH
Step 3 f N.N 0 N
. 0 \ / ¨o..-Sic --S13CN...._c_,,c 6 51d N. Boc H
N1---- = -N 0 -N 0 H2N- i Step 5 N N
¨o- N

aCompound 51 Step 1:
tert-butyl 2-(4-(4-amino-3-(4-phenoxypheny1)- 1 H - py r a zo 1 o [3,4-d]pyrimidin- I -yl)piperidin-l-y1)-7-azaspiro[3.5]nonane-7-carboxylate (51a) \ i N

fi -ThCliCIN.Boc S
3-(4-phenoxypheny1)-1-(piperidin-4-y1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (la) (see I. Med. Chem. 2015, 58, 9625-9638 for the synthetic method) (1.0 g, 2.59 mmol) was dissolved in 35 mL of DCE, and tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-earboxylate (1.24 g, 5.18 mmol) was added, the mixture was stirred at room temperature for 10 min, then sodium triacetoxyborohydride (1.37 g, 6.46 mmol) was added, and the mixture was stirred at room temperature for 16 It To the reaction solution was slowly added 30 mL of saturated sodium bicarbonate aqueous solution, and the mixed solution was extracted with dichloromethane (30 mL x 3). The organic Date Recue/Date Received 2021-09-09 phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) ¨ 20 . 1), to obtain tert-butyl 2-(4-(4-amino-3-(4-phenoxypheny1)- I H-pyrazolo[3,4-d[pyrimidin-1-y1 )piperid in-l-y1)-7-azasp iro [3.5] nonane-7-carboxyl ate (51a) (1.5 g, yield: 95%).
LCMS in/z ¨ 610.4 [M+1]'.
Step 2:
1-(1- (7-azaspiro [3 .5] nonan-2-yl)piperidin-4-y1)-3-(4-phenoxypheny1)- 1H-pyrazolo [3 ,4-d]pyri mi di n-4-am inc trifluoroacetate (51b) N_NO
Tert-butyl 2-(4-(4-ami no-3 -(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimi din-1-yl)piperid in-1 -yI)-7-azaspi ro[3.51nonane-7-carboxy late (51a) (1.5 g, 2.46 min ol) was dissolved in 20 mL of dichloromethane, and 8 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 h. Upon completion of the is reaction, the reaction system was directly concentrated under reduced pressure, to obtain the crude product 1-(1-(1-(7-azaspiro[3.5]nonan-2-yl)piperidin-4-y1)-3-(4-phenoxypheny1)- 1H -pyra zolo[3 ,4-d]pyrimi d in-4-am ine tnifi tioroacetaie (51b) (1.8 g).
LCMS m/z = 510.3 [M4-1[1.
Step 3:
tert-butyl 2 '-(4-(4--amino-3 -(4-phenoxypheny1)-11-1-pyrazolo [3 ,4-d]pyrimidin-1-yl)piperidin-1 -y1)-7,7'-diaza[2,7'-bispiro [3 .5jnonanc]-7-carboxylate (51c) =
"s=N,N

Date Recue/Date Received 2021-09-09 The above crude product 1-(1-(1-(7-azaspiro[3.5]nonan-2-yppiperidin-4-y1)-3-(4-phenoxypheny1)-114-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate (51b) (1.8 g) was dissolved in 40 naL of DCE, and solid sodium bicarbonate (620 mg, 7.38 minol) was added, the mixture was stirred at room temperature for 20 min, then tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (1.18 g, 4.93 mmol) was added, and the mixture was stirred at room temperature for 10 min, then sodium triacetoxyborohydride (1.56 g, 7.36 mmol) was added, and the mixture was stirred at room temperature for 16 h. To the reaction system was slowly added 60 mL of saturated sodium bicarbonate aqueous solution, and the mixed solution was extracted with dichloromethane (80 mL x 3). The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 10: 1), to obtain tert-butyl 2-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazol o [3,4-d]pyrimid 1-yl)p iperid in-1-y1)-7,7'-diaza[2,7t-bispiro[3.5]nonanel-7-carboxylate (51c) (1.2 g, two-step yield calculated from compound 51a: 67%).
LCMS m/z = 733.3 [M+1]-1-.
Step 4:
1-(1-(7,T-diaza[2,71-bispiro [3 .5] nonan]-2'-yl)piperidin-4-y1)-3 -(4-phenoxy -phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (51d) NN

¨( \NNNH

Ten-butyl 2-(4-(4-amino-3-( 4-pbenoxypheny I )- 1 H -pyrazo I o [3 ,4-d]pyrimid in-1-yl)p iperid in-l-y1)-7,7'-cl iaza [2,7'-bispiro [3 .5]nonane]-7-carboxylate (51c) (300 mg, 0.41 mmol) was dissolved in 5 mL of methanol, and 10 mL 2 N ethyl acetate hydrochloride solution was added, the mixture was stirred at room temperature for 4 h. The reaction system was directly concentrated under reduced pressure, to obtain Date Recue/Date Received 2021-09-09 the crude product I -(14 7,7t-diaza[2,71-bispiro[3.5]nonane]-2'-yDpiperidin-4-y1)-3-(4-phenoxypheny1)-114-pyrazolo[3,4-dipyrimidin-4-amine hydrochloride (51d) (0.36 g).
LCMS m/z = 633.5 IM+1,1 .
Step 5:
5-(2r-(4-(4-a1nino-3-(4-phenoxypl1eny1)-1H-pyrazolo [3,4-d]pyrim idi n-1 -yl)piperidin-l-y1)-7, 7'-diaza[2,7-bispiro [3.5]nonan]-7-y1)-2-(2,6-dioxopiperidin-3-ypisoindolinc-1,3 -dione (compound 51) N -CN ¨OCN___OCN

1.11 The above crude product 1-(1-(7,7'-diaza[2,7'-bispiro[3.51nonane]-21-yppiperidin-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (51d) (0.36 g) was dissolved in 25 rnL of DMSO, and solid sodium bicarbonate (138 mg, L64 mmol) was added, the mixture was stirred at mom temperature for 10 min, then 1.5 inL of DIPEA and 2-(2,6-dioxopiperidin-3-y1)-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (166 mg, 0.60 mmol) were added, the reaction was stirred at 80 C for 5 h. The reaction solution was cooled to room temperature, added 50 inL of water, and filtered. The solid was collected, washed with water, and same was dissolved with 50 iriL of dichloromethane, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) ¨ 15 : 1), to obtain 5-(2'-(4-(4-am no-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-di pyrimidi n-1 -yl)pi peridi n-1-yl)-7,7t-diaza[2,7t-bispiro [3 .5jnonan]-7-y1)-2-(2 ,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (compound 51) (120 mg, two-step yield calculated from compound 51c:
33%).
Date Recue/Date Received 2021-09-09 111 NMR (400 MHz, CDC13) 6 8.38 (s, 111), 7.70 - 7.59 (m, 311), 7.43 - 7.34 (m, 214), 7.29 - 7.24 (m, 114), 7.22 - 6.98 (m, 6H), 5.75 (br.s, 21-1), 4.93 (dd, 11-1), 4.84 -4.71 (m, 111), 3.48 - 3.26 (m, 411), 3.09 - 2.98 (in, 2H), 2.93 - 2.80 (in, 2H), 2.79 -2.65 (m, 311), 2.50 - 2.17 (1n, 5H), 2.17- 1.91 (m, 10H), 1.90- 1.48 (m, 12H).
LCMS m/z = 889.5 [M-F-1]' .
Example 52:
5-(2-((3aR,6aS)-5-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-1-Apiperidin-1-Ahexahydroeyelopenta[c]pyrrol-2(1H)-y1)-7-azaspiro[3.5]nonan-7-y1)-2-(2,6-dioxopiperidin-3-Aisoindoline-1,3-dione (compound 52) N---7-,\
Fi2N \ / N

H /

H2N N-,-_\

step I Mt:1)2 i,..
0 '4,N - 0 \H-N...õ1 1,..õ...) 0 \ / ''N-N-CINH a --L,--, , a .# H
o i a 52a 52b NH
H N, Bac I i E 121,i_N17,NN_cw,_,N,_ _oc s:pe 04c 0 HiN \NTN/,NN_cN__,c .. \N
H
Step _, 40 N ______õ !
---OCNH
0 H _.2.
H 52d 52c N.---\
Step d N
.'" ' ----CN _.
N

i.-6 Compound 52 Step 1:
te rt-butyl (3aR,6aS)-5-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-Date Recue/Date Received 2021-09-09 d]pyrimidin-l-yl)piperidin-l-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (52a) N
O&JN N
Boo 3 -(4-phenoxypheny1)-1-(piperidi n-4-y1)-1H-pyrazolo[3 ,4-d]pyrimidin-4-amine (la) (see .1 Med. Chem. 2015, 58, 9625-9638 for the synthetic method) (1.0 g, 2.59 mmol) was dissolved in 35 mL of DCE, and tert-butyl (3aR,6aS)-5-oxo hexahydrocyc1openta[c]pyrrole-2(1H)-carboxylate (1.17 g, 5.19 mmol) was added, the mixture was stirred at room temperature for 10 min, then sodium triacetoxyborohydride (1.37 g, 6.46 mmol) was added, adn the mixture was stirred at room temperature for 16 h. To the reaction solution was slowly added 30 mL of saturated sodium bicarbonate aqueous solution, and the mixed solution was extracted with dichloromethane (30 mL >< 3). The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20 : 1), to obtain tert-butyl (3aR,6aS)-5-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-dlpyrim idin-1-yl)piperidin-l-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (52a) (1.4 g, yield: 91%).
LCMS m/z = 596.4 [M+1]+.
Step 2:
I -(1-((3aR,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)piperi din-4-y1)-3-(4-phenoxypheny1)- I H-pyrazo lo [3 ,4-d]pyrimidin-4-amine tri fluoroacetate (52b) Date Recue/Date Received 2021-09-09 N
0 \ N
NH
Tert-butyl (3aR,6a S)-5-(4-(4-amino -3-(4-phen oxypheny1)-1H-pyrazolo [3,4-d]pyrim idin-1 -yl)piperidin-l-yl)hexahydrocycl openta[c]pyrrole-2(1H)-carboxylate (52a) (1.5 g, 2.52 mmol) was dissolved in 20 mL of DCM, and 8 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 h. Upon completion of the reaction, the reaction system was directly concentrated under reduced pressure, to obtain the crude product 1-(14(3aR,6aS)-octahydrocyclopenta1c]pyiTo1-5-yl)piperidin-4-y1)-3-(4-phenoxypheny1)-11-1-pyrazolo [3 ,4-d] pyritnidin-4-amine trifluoroacetate (52b) (1.6 g).
LCMS m/z = 496.3 1M+1] .
Step 3:
tert-butyl 2-((3 aR,6 aS)-5-(4-(4-amino-3 -(4-phen oxy ph enyI)-1H -pyrazolo [3 4-d]pyrimidin-1-yl)piperidi n-l-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-y1)-7-azaspiro[3.5]nonanc-7-carboxylate (52c) H2N \ /N
N
0 ---OCN-Boc The above crude product 1-(1-((3aR,6aS)-octahych-ocyclopent4c]pyrrol-5-yl)piperidin-4-y1)-3-(4-phenoxypheny1)-1H -pyrazolo [3 ,4-cl] pyrim i di n-4-am inc trifluoroacetate (52b) (0.8 g) was dissolved in 30 mL of DCE, and solid sodium bicarbonate (386 mg, 4.60 mmol) was added, the mixture was stirred at room temperature for 20 min, then tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (550 mg, 2.30 mmol) was added, and the mixture was stirred at room temperature for 10 min, then sodium triacetoxyborohydride (731 mg, 3_45 mmol) was added, and the Date Recue/Date Received 2021-09-09 mixture was stirred at room temperature for 16 h. To the reaction system was slowly added 60 mL of saturated sodium bicarbonate aqueous solution, and the mixed solution was extracted with DCM (80 mL 3). The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) ¨ 10 : 1), to obtain tert-butyl ((3 aR,6aS)-5 -(4-(4-amino-3 -(4-phenoxyphenyI)- I H-pyrazolo [3 ,4-d]pyrimidin- I -yl)piperidin- I -yDhexahydrocyclopenta[c]pyrrol-2 ( 1H)-y1)-7-azaspiro[3.5]nonanc-7-carboxylate (52c) (0.63 g, two-step yield calculated from compound 52a: 70%).
LCMS m/z = 719.5 [M+1] .
Step 4:
I -( I -((3aR,6aS)-2-(7-azaspiro[3 5]nonan-2-ypoetahydrocycl openta[c] pyrrol -yl)piperidin-4 -y1)-3 -(4-phenoxypheny1)-1H-pyrazolo[3 ,4-d]pyrimidin-4-amine hydrochloride (52d) H2N \ /N

Tert-butyl 2-((3aR,6aS)-5-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo [3 ,4-d]pyrimidin- I -yl)piperidin-l-yl)hexahydrocyclopenta[c]pyn-ol-2(1H)-y1)-7-azaspiro[3.5]nonane-7-carboxylate (52c) (300 mg, 0.42 mmol) was dissolved in 5 mL
of methanol, and 10 ml, of 2 mo1/1_ ethyl acetate hydrochloride solution was added, the mixture was stirred at room temperature for 4 h. The reaction system was directly concentrated under reduced pressure, to obtain the crude product I -(1-((3aR,6aS)-2-(7-azaspiro [3 .51nonan -2-yl)octah ydrocyc lopenta [c]pyrrol-5-yl)piperi din-4-y1)-3 -(4-phenoxypheny1)-1 H-pyrazolo[3 A-d]pyrimidin-4-amine hydrochloride (52d) (0.36 g).
LCMS m/z = 619.4 [M+ I ]t Step 5:
5424(3 aR,6aS)-5-(4-(4-amino-3 -(4-phenoxypheny1)-1H -pyrazolo [3 ,4-Date Recue/Date Received 2021-09-09 d]pyrimidin- I -yDpiperidin- 1 -yDhexahydrocyclopenta[c]pyrrol-2( 1H)-y1)-7-azaspiro [3.5] nonan-7-y1)-2-(2,6-dioxopiperidin-3 -yi)isoindoi ine-1,3-dione (compound 52) H2N \ /N

0 N---nrAN
H j 411 = 0 The above crude product 1-( 1-((3aR,6aS)-2-(7-azaspi ro [3.5]nonan yl)octahydrocyclopentalcipyrrol-5-yppiperidin-4-y1)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (52d) (0.36 g) was dissolved in mL of DMSO, and solid sodium bicarbonate (138 mg, 1.64 mmol) was added, the mixture was stirred at room temperature for 10 min, then 1.5 mL of D1PEA and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (166 mg, 0.60 mmol) were added, and the reaction was stirred at 80 C for 5 h. The reaction solution was cooled to room temperature, added 50 mL
of water, and filtered. The solid was collected, washed with water, and same was dissolved with 50 mL of dichloromethane, dried over anhydrous sodium sulphate, is and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) =
15:
1), to obtain 5 -(2-( (3 aR,6aS)-5 -( 4-(4-am ino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4 -d]pyrim id in-l-yl)p iperidin-l-yl)hexahydrocycl openta[c]pyiTo1-2(1H)-y1)-7-azaspiro[3.5]nonan-7-y1)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (compound 52) (100 mg, two-step yield calculated from compound 52e: 27%).
1H NMR (400 MHz, CDC13) 6 10.06 (br.s, 111), 8.39 (s, 1F1), 7.68 - 7.60 (m, 314), 7.42 - 7.34 (m, 214), 7.29 - 7.24 (m, 1H), 7.20 - 6.99 (m, 611), 5.84 (br.s, 2H), 4.98 -4.90 (m, 1H), 4.83 - 4.71 (m, 1H), 3.44 - 3.29 (m, 4H), 3.25 -3.14 (m, 2H), 2.94 -2.66 (m, 414), 2.64- 2.31 (m, 911), 2.30- 2.07 (m, 5H), 2.07- 1.93 (m, 4H), 1.89 -1.59 (m, 6H), 1.46- 1.32 (m, 2H).
LCMS m/z = 875.4 [M+1]+.
Date Recue/Date Received 2021-09-09 Example 53:
5-((3aR,31aR,6aS,6'aS)-5-(4-(4-amino-3-(4-phenoxypheny1)-111-pyrazolo[3,4-d]pyrimidin- 1 -y Opiperidin- 1-yl)dodecahydro- 1H-L2,5'-bi(cyclopenta[c]pyrrol)]-2( I 'H)-y1)-2-(2,6-dioxopiperidin-3-yOisoindoline- 1,3-dione trifluoroacetate (compound 53) c) 0 H / N
g H
N-ZiciN ---- o N----t://H o H
N, _CNN---(7/
--- , N --/ H
\ H2N/N
N=7 Q H H
AL
ir---VINH 2 ___4(:=VINBoc 0 , N __ON--- H
Step I 0-_ -N.- N N---C-VH
N
- \---' H Step 2 Mr _11 ¨).-H2N---- , N=/
52b 533 0o g iciH
(2 i-XIN --- N ---?--- NH
H
___/0 N N
__CIN H H 0- 0 N Step 3 110 H N

H2N¨c"N
N-/ 53b / Compound 53 NI¨

Step 1:
tert-butyl (3aR,3aR,6aS,61aS)-5-(4-(4-amino-3-(4-phenoxypheny1)-pyrazolo[3 ,4-dlpyrimidin- 1 -yl)piperidin-1 -yl)dodecahydro- 1 H-[2,5'-bi(cyc lopenta[cipyrrole)]-2'(11-1)-earboxylate (53a) H
q _,..._ici i,SC/NBoc-N
H
0 / \ N, _CN
---- -- N / H
µ1,1 The above crude product 1-(1-((3aR,6aS)-octahydrocyclopenta[c]pyn-o1-5-yppiperidin-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine Is trifluoroacetate (52b) (0.5 g) was dissolved in 30 nilL of DCE, and solid sodium bicarbonate (386 mg, 4.60 mmol) was added, the mixture was stirred at room Date Recue/Date Received 2021-09-09 temperature for 20 min, then tert-butyl (3aR,6aS)-5-oxo hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.45 g, 2.0 mmol) was added, and the reaction was continued at 40'C for 1 Ii, then sodium triacetoxyborohydride (0.42 g, 2.0 mmol) was added, and the mixture was stirred at room temperature for 16 h. To the reaction system was slowly added 60 mL of saturated sodium bicarbonate aqueous solution, and the mixed solution was extracted with DCM (80 nit x 3).
The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 10 : 1), to obtain tert-butyl (3aR,3'aR,6aS,6'aS)-5-(4-(4-amino-3-(4-phenoxypheny1)- I H-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-1-yl)dodecahydro-[2,5t-bi(cyc1openta[c]pyrrole)j-21(1'H)-carboxylate (53a) (0.25 g, two-step yield calculated from compound 52a: 45%).
LCMS rn/z = 705.5 [M+1]+.
Step 2:
3-(4-phenoxypheny1)-1-(14(3aR,3taR,6aS,6taS)-tetradecahydro-IH-[2,5'-bi(cyclopenta[c]pyrrol)]-5-yppiperidin-4-y1)-1H -pyrazolo [3 ,4 -d]pyrimidin-4 -ami ne trifluoroacetate (53b) H2N).
N=7 Tert-butyl (3 aR,3taR,6aS,CaS)-5-(4-(4-amino-3-(4 -phenoxypheny1)-111-pyrazolo [3 ,4-d}pyrim idin-l-yl)piperidin-l-yl)dodecahydro-1H-[2,5'-bi(cy clopenta[c]py rrole)]-2'(1`H)-carboxy late (53a) (0.25 g, 0.35 mmol) was dissolved in 8 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 4 h. The reaction system was concentrated under reduced pressure, to obtain the crude product 3-(4-phenoxypheny1)-1-( I -((3aR,3taR,6aS,6'aS)-tetradecahydro-1H-[2,5'-bi(cyclopenta[elpyrrol)]-5-yl)piperidin-4-y1)-1H -pyrazolo[3,4-d]pyrimidin-4-arnine Date Recue/Date Received 2021-09-09 trifluoroacetate (53b) (0.2 g).
LCMS m/z = 605.4 [M+1]+.
Step 3:
5-( (3aR,3'aR,6aS,6'aS)-5-(4-(4-amino-3 -(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin- I -yl)piperidi n-l-yl)dodecahydro-1H-[2,5'-bi(cyclopenta[c]pyrrol)]-2'(11-1)-y1)-2-(2,6-di oxopiperi din-3 -yl)isoindoline-1,3 -dione trifluoroacetate (compound 53) o 0 N
Qo 'N'NO
H2N \N
N=/
The above crude product 3-(4-phenoxypheny1)-1-(14(3aR,3TaR,6aS,6taS)-tetradecahydro-11142,5'-bi(cyclopenta[c]pytTol)]-5-y1)piperidin-4-y1)-114-pyrazolo[3,4-d]pyrimidin-4-amine trifluoroacetate (53b) (0.32 g) was dissolved in 10 mL of DMSO, and solid sodium bicarbonate (0.14 g, 1.67 mmol) was added, the mixture was stirred at room temperature for 10 min, then DIPEA (0.13 g, 1.0 mmol) and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO

is for the synthetic method) (0.12 g, 0.43 mmol) were added, and the reaction was carried out at 90 C for 4 h. The reaction solution was cooled to room temperature, and 50 inL of ethyl acetate and 50 mL of water were added. The organic phase was separated, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) ¨ 15 : 1), to obtain 5-((3 aR,3`aR,6aS,6taS)-5-(4-(4-amino-3-(4-phenoxypheny1)-1H -pyrazo lo [3 ,4-d]pyrimidin- 1-yl)piperidin-l-yl)dodecahydm-1H42,5'-bi(cyclopenta [c]pyrro 2'(1'H)-y1)-2 -(2 ,6-di oxopiperidin-3 -y 1) iso indolin e-1,3 -dione trifluoroacetate (compound 53) (50 mg).
'H NMR (400 MHz, CDC13) 6 8.56 (br.s, 1H), 8.36 (s, 1H), 7.67 - 7.60 (m, 311), 7.42 - 7.34 (in, 2H), 7.20 - 7.04 (in, 51-1), 6.95 (d, 111), 6.69 (dd, 1H), 5.56 (br.s, 211), 4.92 (dd, 111), 4.84 - 4.70 (in, Hi), 3.62 - 3.52 (in, 2H), 3.43 - 3.35 (in, 211), 3.26 -Date Recue/Date Received 2021-09-09 3.13 (m, 211), 2.94- 2.37 (m, 1511), 2.37 - 1.93 (m, 1311).
LCMS miz = 861.4 [M4-1]+.
Example 54:
5-(7-(3-(4-(4-amino-3-(4-phenoxypheny1)- I H-pyrazolo[3,4-d jpyrimidin-1-yl)piperidin-l-yl)azetidin-l-y1)-2-azaspiro[3.5]nonan-2-y1)-2-(2,6-dioxop iperidin-3-yl)isoindoline-1,3-dione (compound 54) Fi2N /N
o H
0 _r_to /N
Step I Step2 N N
O
0 \
4.
17b 54a N-Boc N
H2N \ / H2N 4/.4 Si,p 3 --OCN H ,N -C 0 H

54b Compound 54 /

Step 1:
io tert-butyl 7-(3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-1 -yl)piperi di n-l-ypazeti din-l-y1)-2-azaspiro [3 .5]nonane-2-carboxylate (54a) H2N \ /
, N¨Boc 1- [ 1-(azetidin-3-y1)-4-piperidy11-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine (17b) (1.0 g, 2.26 mmol) was dissolved in 30 mL of DCE, and Date Recue/Date Received 2021-09-09 tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate (0.82 g, 3.43 mmol) was added, the mixture was stirred at room temperature for 10 min, then sodium triacetoxyborohydride (1.2 g, 5.66 mmol) was added, and the mixture was stirred at room temperature for 16 h. To the reaction system was slowly added 60 mL of saturated sodium bicarbonate aqueous solution, and the mixed solution was extracted with DCM (80 itiL x 3). The organic phase was washed with 50 inL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 10 : 1), to obtain tert-butyl 7-(3-(4-(4-amino-3-(4-ph enoxyph eny1)-1H-pyrazol o [3 ,4-d]pyrim idin-l-yl)p iperidin- I -yl)azetidin-l-y1)-2-azaspiro[3.51nonane-2-carboxylate (54a) (1.2 g, yield: 80%).
LCMS m/z = 665.3 [M+ l].
Step 2:
I -( I -(1-(2-azaspiro[3 .5] nonan-7-yl)azeti d in-3-yl)piperidin-4 -y1)-3-(4-phenoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (54b) H2N \ /
N
N H

T ert- bu ty I 7-(3-(4-(4-ami no-3-(4-ph enoxyphenyI)-1H-pyrazolo[3,4-d]pyrimid in- I -yl)piperidin- I -yl)azetidin-1-y1)-2-azaspiro[3 5] nonane-2-carboxylate (54a) (300 mg, 0.45 mmol) was dissolved in 5 mL of methanol, and 10 mL of 2 mol/L
ethyl acetate hydrochloride solution was added, the mixture was stirred at room temperature for 4 h. The reaction system was directly concentrated under reduced pressure, to obtain the crude product I -(1-( -(2-(azaspiro[3.5inonan-7-yl)azeti din-3-y 1)piperidin -4 -y1)-3-(4-phenoxypheny1)- I H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (54b) (0.35 g).
LCMS m/z = 565.4 [M+1r.
Step 3:
Date Recue/Date Received 2021-09-09 5-(7-(3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazo lo [3 ,4-d]pyrim idin-1-yl)piperidin-1 -yl)azetidin-1 -y1)-2-azaspiro [3 .5]nonan-2-y1)-2-(2,6-dioxop iperidin-3-yl)iso indo1ine-1,3- dione (compound 54) N=--\
H2N iN

NNY

= 0 The above crude product 1-(1-(1-(2-(azaspiro[3.5]nonan-7-yl)azetidin-3-yl)p iperid in-4 -y1)-3-(4-phenoxyphe ny1)-1 H-pyrazolo [3 ,4-d] pyr im id i n-4-am ine hydrochloride (54b) (0.35 g) was dissolved in 25 mL of DMSO, and solid sodium bicarbonate (152 mg, 1.81 mmol) was added, the mixture was stirred at room temperature for 10 min, then 1.5 mL of D1PEA and 2-(2,6-dioxopiperidin-3-y-5-(see WO 2017197056 for the synthetic method) (186 mg, 0.67 mmol) were added, and the reaction was stirred at 80 C for 5 h. The reaction solution was cooled to room temperature, added 50 mL of water, and filtered.
The solid was collected, washed with water, and same was dissolved with 50 mL of dichloromethane, dried over anhydrous sodium sulphate, and concentrated under is reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 15 : 1), to obtain 5-(7-(3-(4-(4-am ino-3-(4-phenoxypheny1)- 1H-pyrazolo[3,4-d]pyrim idi n-l-yl)piperidin-1-y 1)azetidin-l-y1)-2-azaspiro [3 .5 ]nonan-2-y1)- 2-(2,6-dioxopiperidin-3-yflisoindoline-1,3-dione (compound 54) (95 mg, two-step yield calculated from compound 54a: 26%).
1H NMR (400 MHz, CDC13) 6 9.23 (br.s, 1H), 8.38 (s, 1,H), 7.68 - 7.59 (m, 311), 7.43 - 7.35 (m, 211), 7.21 - 7.11 (in, 311), 7.11 - 7.05 (in, 2H), 6.76 (d, 1H), 6.49 (dd, 111), 5.64 (br.s, 2H), 4.93 (dd, 1H), 4.84- 4.72 (m, 1H), 3.78 - 3.56 (m, 6H), 3.15 -2.65 (m, 811), 2.49 - 2.36 (m, 211), 2.16 - 1.94 (m, 8H), 1.81 - 1.72 (m, 2H), 1.59 -1.49 (m, 211), 1.26 - 1.16 (m, 2H).
LCMS m/z = 821.4 [M+1]+.
Date Recue/Date Received 2021-09-09 Example 55:
5-(7-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-1-Apiperidin-1-y1)-2,2'-diaza[2,7T-bispiro[3.5]nonan]-2t-y1)-2-(2,6-dioxopiperidin-3-yinsoindoline-1,3-dione (compound 55) H
N,-------\N 0 N_ _.-0 0 1.........õ-__7.--H2N \ 1 N
N

lel mcp I
_________________________ r 0 Ctep 2 OH a 0 0 la 55a ' 1 N,Boc 55b 'CDC
\NH
N.--", N--,---,,, H.,NA.2(N
H2N \ iN
Stup 4 s'eP 3 ______________________ a )\I-N1---CN p Step 5 --,--0--11111: N 0 N
. 55c N-Bõo `=, i 55d -N.---,õ

'N-N-C\N_ 0 H
N
N Compound 55 o Step 1:
tert-butyl 7-(4-(4-amino-3-(4-phenoxyphenyI)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-l-y1)-2-azaspiro[3.5]nonane-2-carboxylate (55a) Date Recue/Date Received 2021-09-09 N N
N
CbN , Boc 3 -(4-phenoxypheny1)-1-(piperidi n-4 -y1)-1H-pyrazolo [3 ,4-d] pyrim idin-4 -amine (1a) (see J Med. Chem. 2015, 58, 9625-9638 for the synthetic method) (1.0 g, 2.59 mmol) was dissolved in 35 mL of DCE, and tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate (0.93 g, 3.89 mmol) was added, the mixture was stirred at room temperature for 10 min, then sodium triacetoxyborohydride (1.37 g, 6.46 mmol) was added, and the mixture was stirred at room temperature for 16 h. To the reaction solution was slowly added 30 mL of saturated sodium bicarbonate aqueous solution, and the mixed solution was extracted with DCM (30 mL x 3). The organic phase was washed with 50 mt., of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) -= 20 : 1), to obtain tert-butyl 7-(4-(4-amino-3-(4-phenoxypheny1)- I H -pyrazolo43,4 -(1] pyrimidin-1-yppiperidin-l-y1)-2- azaspiro[3 .5]nonane-2-carboxy1ate (55a) (1.4 g, yield:
89%).
LCMS m/z = 610.4 [M-F1]+.
Step 2:
1-(1-(2-azaspiro[3.5]nonan-7-y Dpiperidin-4-y1)-3-(4-phenoxyphe ny1)-1H-pyrazolo[3 ,4-d] pyrirnidin-4- amine hydrochloride (55b) N

N
ICbNH
Tert-butyl 7-(4-(4-amino-3-(4-phenoxypheny1)- I H-pyrazolo [3,4-d]pyrimidin-1 -yl)pipetidin- 1 -y1)-2-azaspiro [3 .51nonane-2-earboxy1ate (55a) (1.4 g, 2.30 mmol) was dissolved in 5 mL of methanol, and 25 mL of 2 mol/L ethyl acetate hydrochloride Date Recue/Date Received 2021-09-09 solution was added, the mixture was stirred at room temperature for 4 h. Upon completion of the reaction, the system was directly concentrated under reduced pressure, to obtain the crude product 1-(1-(2-azaspiro[3.5]nonan-7-y1)piperidin-4-y1)-3-(4-phenoxypheny1)- I H-pyrazolo[3,4-d jpyrimidi n-4-amine hydrochloride (55b) ( 1.5 g).
LCMS ni/z ¨ 510.3 [M+1]'.
Step 3:
tert-butyl 7-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidi n-1 -yI)-2,2'-di aza[2,7'-bispiro[3 .5]nonane]-2'-earboxylate (55c) N=\

N

The above crude product 1-(1-(2-azaspiro[3.5]nonan-7-yl)piperidin-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3 ,4-d]pyritnidin-4-aminc hydrochloride (55h) (0.8 g) was dissolved in 40 mL of DCE, and solid sodium bicarbonate (330 mg, 3.93 rrimol) was added, the mixture was stirred at room temperature for 20 min, tert-butyl 7-oxo-1. 2-azaspiro[3.5]nonane-2-carboxylate (0.47 g, 1.96 mmol) was added, and the mixture was stirred at room temperature for 10 min, then sodium triacetoxyhorohydride (0.70 g, 3.30 mmol) was added, and the mixture was stirred at room temperature for 16 h.
To the reaction system was slowly added 60 mL of saturated sodium bicarbonate aqueous solution, and the mixed solution was extracted with DCM (80 mL x 3).
The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) ---- 10 1), to obtain tert-butyl 7-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-1-y1)piperidin-1-y1)-2,2'-diaza[2,7t-hispiro[3.5]nonane]-2'-carboxylate (55e) (0.70 g, two-step yield calculated from compound 55a: 78%).
LCMS m/z = 733.3 [M+1].
Date Recue/Date Received 2021-09-09 Step 4:
141 -(2,2'-diaza[2,71-bispiro [3 .5] nonan ]-7-yl)piperidin-4-y1)-3 -(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (55d) N--=\

N
N-Tert-butyl 7-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-l-y1)piperidin-1-y1)-2,2'-diaza[2,7T-bispiro[3.5]nonane]-2'-carboxylate (55c) (300 mg, 0.41 mmol) was dissolved in 5 mL of methanol, and 15 mL of 2 mol/L ethyl acetate hydrochloride solution was added, the mixture was stirred at room temperature for 4 h. The reaction system was directly concentrated under reduced pressure, to obtain the crude product 1-(1-(2,2'-diaza[2, 7'-bispiro[3.51nonan-y I ] piperid in -4 -y1)-3-(4-phenox yphen y1)- 111-pyra zo lo [3 ,4-d]pyrim id in -4-a m in e hydrochloride (55d) (0.32 g).
LCMS m/z = 633.5 [M+1]4.
Step 5:
is 54744- (4-amino-3-(4-phenoxypheny1)-1 H-pyrazolo [3,4-d]pyrimidi n-1 -yl)piperi di n-1 -y1)-2,2'-di aza[2,7'-bi spirop .51nonan]-2'-y1)-2-(2,6-dioxopi peri din-3-soi ndo n e-1,3- dione (compound 55) H2N \
\N
N / -OCN-OCN N

The above crude product 1 -(1 -(2,2'-diaza[2,7t-bi spi ro [3 .5]nonan-7-yl]
piperi di n-4-y1)-3 -(4-phenoxypheny1)-1H-pyrazolo [3,4-d] pyrimi di n-4-am ine hydrochloride (55d) (0.32 g) was dissolved in 25 mL of DMSO, and solid sodium bicarbonate (138 mg, 1.64 mmol) was added, the mixture was stirred at room temperature for 10 min, then 1.5 mL of DIPEA and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-Date Recue/Date Received 2021-09-09 dione (see WO 2017197056 for the synthetic method) (166 mg, 0.60 mmol) were added, and the reaction was stirred at 80 C for 5 h. The reaction solution was cooled to room temperature, added 50 mL of water, and filtered. The solid was collected, washed with water, and same was dissolved with 50 mL of dichloromethane, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 15 : 1), to obtain 5-(7-(444-amino-3-(4-phenoxypheny1)-1H-pyrazo lo[3 ,4-djpyrimidin-1-y1)piperidin-1 -y1)-2,2'-diaza[2,7!-bispiro[3.5jnonan] -2T-y1)-2 -(2,6-di oxopiperidin-3 -yl)i soi ndoli ne-1,3-dione (compound 55) (70 mg, two-step yield calculated from compound 55c: 19%).
11-1NMR (400 MHz, CDC13) 6 9.13 (br.s, 1H), 8.38 (s, 1H), 7.71 -7.57 (n, 3H), 7.43.. 7.33 (n, 2H), 7.22 - 7.02 (n, 5H), 6.76 (d, 11-1), 6.49 (dd, I H), 5.62 (br.s, 21-1), 4.97 - 4.88 (in, 1H), 4.83 - 4.68 (m, 1H), 3.76 - 3.60 (in, 4H), 3.40 - 2.60 (n, 9H), 2.50- 2.26 (m, 5H), 119 - 1.92 (in, 8H), 1.88- 1.70(m, 4H), 1.58- 1.41 (n, 4H), 1.35 - 1.23 (in, 4H).
LCMS m/z = 889.4 [M. 1]'.
Example 56:
5 -( 3-(7-(4-(4-amino-3 -(4-phenoxypheny1)-1H-pyrazolo [3 ,4-d]pyrim idin -1 -yl)piperidin-1 -y1)-2-azaspiro [3.5]nonan-2-yl)azetidin-1 -y1)-2-(2,6-dioxopiperidin-3-ypisoindoline-1,3-dione (compound 56) H

-N,N¨CN¨OC

Date Recue/Date Received 2021-09-09 cl%
Ntd g4"====".. Step 1 Step 2 -N
=--'"" -VNH
N-ecc 5511 56 a A
0'r 1,0 .;
- E "
Step 3 N

c .
5Erb C11' Compound 56 Step 1:
tert-butyl 3-(7-(4-(4-am ino-3-(4-phenoxyphen y1)-1H-pyrazolo [3,4-dipyrim idin-l-yl)piperidin-l-y1)-2-azaspiro [3.5]nonan-2-yl)azetidine-l-carboxylate (56a) H2N /1`1 N

1-(1-(2-azaspiro[3.5]nonan-7-y1)piperidin-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-dlpyrimidin-4-amine hydrochloride (55b) (0.6 g) was dissolved in mL of DCE, and solid sodium bicarbonate (247 mg, 2.94 mmol) was added, the mixture was stirred at room temperature for 20 min, then tert-butyl 3-oxoazetidine-1 -carboxylate (337 mg, 1.97 mrnol) was added, the mixture was stirred at room temperature for 10 min, then sodium triacetoxyborohydride (0.52 g, 2.45 rnmol) was added, and the mixture was stirred at room temperature for 16 h. To the reaction system was slowly added 60 mL of saturated sodium bicarbonate aqueous solution, is and the mixed solution was extracted with DCM (80 mL x 3). The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 10 : 1), to obtain tert-butyl 3-(7-(4-(4-amino-3-(4-phenoxyphenyl )-1H-pyrazol o [3,4-d jpyrimidin-1 Date Recue/Date Received 2021-09-09 yl)piperidin-l-y1)-2-azaspiro[3.5]nonan-2-yl)azetidine-1-carboxylate (56a) (0.44 g, two-step yield calculated from compound 55a: 72%).
LCMS tri/z ¨ 665.4 [M-Fl ]+.
Step 2:
1 --(1-(2-(azetidin-3-y1)-2-azaspiro[3.5]nonan-7-yl)piperidin-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d[pyrimidin-4-amine hydrochloride (56b) N7,--=\N
H2N \ /
"-CNNN -=

Tert-butyl 3-(7-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin- I -y1)-2-azaspiro[3.5]nonan-2-ypazetidine-1-carboxylatc (56a) (250 mg, 0.38 mmol) was dissolved in 5 mL of methanol, and 15 mL of 2 mol/L
ethyl acetate hydrochloride solution was added, the mixture was stirred at room temperature for 4 h. The reaction system was directly concentrated under reduced pressure, to obtain the crude product 1-(1-(2-(azetidin-3-y1)-2-azaspiro[3.5]nonan-7-yl)piperidin-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (56b) (0.28 g).
LCMS m/z = 565.1 [M 1].
Step 5:
5-(3-(7-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3 ,4-d]pyrimidin-1-yl)piperidin-l-y1)-2-azaspiro [3 .5 [nonan-2-y Daze tidin-l-y1)-2-(2 ,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (compound 56) 1 - 1-(2-(azetidin-3-y1)-2-azaspiro[3.5]nonan-7-yl)piperidin-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (56b) (0.28 g) Date Recue/Date Received 2021-09-09 was dissolved in 15 mL of DMSO, and solid sodium bicarbonate (127 mg, 1.51 mmol) was added, the mixture was stirred at room temperature for 10 min, then 1.5 mL
of DIPEA and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO
2017197056 for the synthetic method) (157 mg, 0.57 mmol) were added, and the reaction was stirred at 80 C for 5 h. The reaction solution was cooled to room temperature, added 50 rtiL of water, and filtered. The solid was collected, washed with water, and same was dissolved with 50 mL of dichloromethane, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 15 : 1), to obtain 5-(3-(7-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazo lo [3 ,4-d]pyrim idin-l-yl)piperid in-l-y1)-2-azaspiro [3.5jn0nan-2-yl)azetidin-1 -y1)-2-(2,6- dioxopiperidin-3-yl)iso indo line-1,3-dione (compound 56) (110 mg, two-step yield calculated from compound 56a:
35%).
II4 NMR (400 MHz, CDC13) .6 9.64 (br.s, 1H), 8.38 (s, 1H), 7.68 - 7.59 (m, 31-1), 7.42 - 7.34 (m, 2H), 7.20 - 7.10 (m, 3H), 7.10- 7.04 (m, 2H), 6.77 (d, 114), 6.50 (dd, 1H), 5.75 (br.s, 214), 4.92 (dd, 111), 4.85 -4.68 (in, 111), 4.07 - 3.96 (m, 211), 3.88 -3.78 (m, 211), 3.72 - 3.62 (m, 1H), 3.20 - 2.96 (m, 6H), 2.92 - 2.65 (m, 3H), 2.58 -2.28 (m, 514), 2.17 - 2.07 (m, 21-1), 2.07 - 2.03 (m, 2H), 2.03 - 1.97 (m, 1H), 1.91 -1.81 (m, 214), 1.53 - 1.42 (m, 2H), 1.39- 1.30 (m, 211).
LCMS m/z = 821.2 [M+1] .
Example 57:
5-(3-(3-(4-(4-amino-3 -(4-plienoxypheny1)-1H-pyrazolo[3 ,4-d]pyrim idin-1-yl)piperidin-1 -y1)-8-azab icyc lo [3 .2 .1]octan-8-ypazetidin-l-y1)-2-(2,6-dioxop iperidin-3-ypisoindoline-1,3-dione (compound 57) Date Recue/Date Received 2021-09-09 W.\ H2N
H2N N H2NNBoc O NH

Step 3 NN-N
0 n, la 57a 57b N¨( µ'N N¨N-Boc N¨CN N¨CN-H
Step 4 Step 5 o 57c 57d N,,,0 N
Compound 57 Step 1:
tert-butyl 3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-d]pyrimid in- I -y 1)piperidin-1 -y1)-8-azab icyc lo[3 .2 .1]octane-8- carboxy late (57a) N
H2N- µ-===
µNN¨aBoc 3 -(4-phenoxypheny1)-1-(piperidin-4 -yI)-1I I-pyrazo I o [3 ,4-d] pyrim idin-4 -am ine (la) (see J. Med. Chem. 2015, 58, 9625-9638 for the synthetic method) (5.0 g,

12.94 mmol) was dissolved in 85 mL of DCE, and tert-butyl 3-oxo-8-azabicyclo[3.2.1loctanc-8-carboxylate (5.82 g, 25.83 mmol) was added, the reaction was stirred at 55 C for 2 h, and then cooled to room temperature. Sodium triacetoxyborohydride (8.23 g, 38.83 mmol) was added, and the mixture was stirred at room temperature for 16 h. To the reaction solution was slowly added 100 triL of saturated sodium bicarbonate aqueous solution, and the mixed solution was extracted with DC M (120 ml, x 3). The organic phase was washed with 150 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude Date Recue/Date Received 2021-09-09 product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20 : 1), to obtain tert-butyl 3-(4-(4-(4-amino-3-(4-phenoxypheny1)- 1H-pyrazolo [3 ,4-d]py rimidin-l-y 1)piperidin-l-y1)-8-azabicyclo[3.2.1joctane-8-carboxylate (57a) (0.4 g, yield: 5%).
1H NMR (400 MHz, CDC13) 6 8.36 (s, 1H), 7.68 - 7.61 (m, 2H), 7.42- 7.35 (m, 2H), 7.21 - 7.05 (iii, 5H), 5.53 (br.s, 2H), 4.85 - 4.65 (m, 1H), 4.40 - 4.15 (m, 2H), 3.18- 2.99 (m, 2H), 2.98- 2.82 (m, 1H), 2.48 - 2.30 (m, 4H), 2.11 - 1.91 (m, 4H), 1.83 - 1.59 (m, 6H), 1.47 (s, 9H).
LCMS m/z = 596.4 [M
Step 2:
1-(1-(8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-y1)-3 -(4-phenoxypheny1)- 1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (57b) -N
H2N ===
N
Tert-butyl 3-(4-(4-(4-amino-3 -(4-phenoxypheny1)-1H-pyrazo 1o[3 ,4-Is d]pyrimidin-1 -yl)piperidin-1 -y1)-8-azabicyclo [3 .2.1]octane-8-carboxylate (57a) (0,38 g, 0.64 mmol) was dissolved in 5 inL of methanol, and 25 mL of 2 mol/L
ethyl acetate hydrochloride solution was added, the mixture was stirred at room temperature for 4 h. Upon completion of the reaction, the system was directly concentrated under reduced pressure, to obtain the cnide product 1-(1-(8-azabi cyclo [3.2.1 octan-3-yl)piperidin-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-d]pyrimidin-4-amine hydrochloride (57b) (0.4 g).
LCMS m/z = 496.3 [M+1] .
Step 3:
tert-butyl 3 -(3 -(4-(4-amino-3 -( 4-phenoxypheny1)-1 H -pyrazolo [3 ,4 -d]pyrimidin- 1-yl)piperidin-1-y1)-8-azabicycl o[3 .2.1]octan-8-yl)azetidine-1 carboxylate (57c) Date Recue/Date Received 2021-09-09 N¨( \NJ N¨CN¨Boc The above crude product 1-(1-(8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-y1)-3-(4-phenoxypheny1)- I H-pyrazolo[3,4-djpyrimidin-4-amine hydrochloride (57b) (0.17 g) was dissolved in 20 mL of DCE, and solid sodium bicarbonate (96 mg, 1.14 mmol) was added, the mixture was stirred at room temperature for 20 min, then N-Boc-azetidinone (96 mg, 0.56 mmol) was added, the mixture was stirred at room temperature for 10 min, then sodium triacetoxyborohydride (0.18 g, 0.85 mmol) was added, and the mixture was stirred at room temperature for 16 h. To the reaction system was slowly added 20 mL of saturated sodium bicarbonate aqueous solution, and the mixed solution was extracted with DCM (50 mL x 3). The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 10 : 1), to obtain tert-butyl 3- (3 -(4-(4- amino-3- (4-phenoxypheny1)- I H-pyrazolo[3,4-d]
pyrinaidin-1 is yl)piperidin-1 -y1)-8-azabicyclo[3 .2.1 loctan-8-yl)azetidine-1 -carboxylate (57c) (0.16 g, two-step yield calculated from compound 57a: 90%).
LCMS m/z ¨ 651.4 [M+ Ir.
Step 4:
I -(1-(8-(azetidin-3 -yI)-8-azabicyclo [3.2.1 joctan-3 -yl)piperidin-4-yI)-3 -(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (57d) \N-01¨CN¨H

Tert-butyl 34344 -(4-amino-3 -(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyr im idin-1 -yl)p iperidin-l-y1)-8-azabicyclo [3 .2.1]octan-8-yl)azetidine-Date Recue/Date Received 2021-09-09 carboxylate (57c) (150 mg, 0.23 mmol) was dissolved in 5 mL of methanol, and mL of 2 mol/L ethyl acetate hydrochloride solution was added, the mixture was stirred at room temperature for 4 h. The reaction system was directly concentrated under reduced pressure, to obtain the crude product 1-(1-(8-(azetidin-3-y1)-8-azabi cyc lo [3.2.1}octan-3-yl)piperi di n-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo [3 ,4-d]pyrimidin-4-amine hydrochloride (57d) (0.16 g).
LCMS m/z = 551.3 [M+1]+.
Step 5:
5-(3-(3-(4-(4-amino-3-(4-phenoxypheny1)-111-pyrazolo [3 ,4-d]pyrimidin- 1-yl)piperidin-l-y1)-8-azabicyclo[3.2.1 ]oetan-8-yl)azetidin-l-y1)-2-(2,6-dioxopiperidin-3-y1)isoindoline-1,3-dione (compound 57) O NO

The above crude product 1-(1-(8-(azetidin-3-y1)-8-azabicyclo[3.2.1joctan-3-yppiperidin-4-y1)-3-(4-phenoxypheny1)-1H-pyrazo lo [3 ,4-d] pyrimidin-4-amine is hydrochloride (57d) (0.16 g) was dissolved in 10 mL of DMSO, and solid sodium bicarbonate (78 mg, 0.93 mmol) was added, the mixture was stirred at room temperature for 10 min, then 1.0 mL of DIPEA and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (95 mg, 0.34 mmol) were added, and the reaction was stirred at 80 C for 5 h. The reaction solution was cooled to room temperature, added 50 mL of water, and filtered.
The solid was collected, washed with water, and same was dissolved with 50 mL of dichloromethane, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 15 : I), to obtain 543-(3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-1-y1)piperidin-1-y1)-8-azabicyclo[3.2.1]octan-8-y1)azetidin- I -y1)-2-(2,6-dioxop iperidin-3-Date Recue/Date Received 2021-09-09 yl)isoindoline-1,3-dione (compound 57) (80 mg, two-step yield calculated from compound 57c: 43%).
1H NMR (400 MHz, CDC13) 6 9.30 (br.s, 1H), 8.38 (s, 1H), 7.68 - 7.59 (m, 3H), 7.43 - 7.34 (m, 2H), 7.21 - 7.03 (m, 5H), 6.77 (d, 1H), 6.50 (dd, 1H), 5.68 (br.s, 2H), 4.92 (dd, 11-1), 4.83 - 4.67 (m, 1H), 4.18 - 4.04 (m, 2H), 3.86- 3.77 (m, 2H), 3.76 -3.62 (in, 1H), 3.36 - 3.26 (in, 2H), 3.22 - 3.03 (iii, 2H), 2.93 - 2.65 (in, 4H), 2.51 -2.27 (m, 4H), 2.17 - 1.92 (m, 5H), 1.84 - 1.60 (m, 6H).
LCMS m/z = 807.1 [M+1] .
Example 58:
5-(3-(4-(4-am no-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-d]pyrim i di n-1-yl)piperidin-l-y1)-8-azabicyclo[3 .2 .1]octan-8-y1)-2-(2,6-di oxopiperidin-3 -yl)isoindoline-1,3-dione (compound 58) 0 711.I

N

0,, 14.

N

\-1 Step 1 r , 57b Compound 58 The above crude product 1-(1-(8-azabicyclo[3.2.11octan-3-y1)piperidin-4-y1)-3-(4-phenoxypheny1)-111-pyrazolo[3,4-dipyrimidin-4-amine hydrochloride (57b) (0.2 g) was dissolved in 10 mL of DMSO, and solid sodium bicarbonate (113 mg, 1.35 mmol) was added, the mixture was stirred at room temperature for 10 min, then 1.0 mi, of D1PEA and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (139 mg, 0.50 mmol) were added, and the reaction was stirred at 80 C for 5 h. The reaction solution was cooled to room Date Recue/Date Received 2021-09-09 temperature, added 20 mL of water, and filtered. The solid was collected, washed with water, and same was dissolved with 50 mL of dichloromethane, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 15 : 1), to obtain 5-(3-(4-(4-amino-3-(4-phenoxypheny1)- I H-pyrazolo[3,4-djpyrinndin-1-yOpiperidi n- I -yI)-8-azabicyclo[3 .2. l]octan-8-y1)-242,6-dioxopiperidin-3 soindoline-1,3 -di one (compound 58) (110 mg, two-step yield calculated from compound 57a: 46%).
III NMR (400 MI lz, CDC13) 6 9.06 (br.s, 111), 8.36 (s, 111), 7.70 - 7.64 (m, 111), 7.64- 7.58 (in, 2H), 7.41 -7.33 (m, 2H), 7.19 - 7.03 (in, 6H), 6.92 (dd, I H), 5.64 (br.s, 2H), 4.97 - 4.89 (m, 1H), 4.77 - 4.64 (m, 1H), 4.47 - 4.39 (m, 211), 3.10 -2.65 (m, 611), 2.42 -2.24 (m, 41-1), 2.18 - 2.08 (in, 3H), 2.04- 1.94 (m, 211), 1.92 -1.82 (m, 211), 1.82- 1.74 (in, 4H).
LCMS m/z = 752.3 [M+1]+.
Example 59:
543 -((3aR,6aS)-5-(4-(4-am no-3-(4-phenoxyphenyI)- I H-pyrazolo [3 ,4-d]pyrim idin-1 -yl)piperidin- I -yphexahydrocyclopenta[c]pyrrol-2( I H)-yl)azetidin- I -y1)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (compound 59) 1\1"¨CN

0= N, 0 0 N, N=/
Date Recue/Date Received 2021-09-09 H St,Tr2 / \N
N¨/ N¨( H,N 912"N
2b 59a 599 <,:cp N, 3 1,r_c-V71 ¨ 0 H
*
H
Compound 59 Step 1:
tert-butyl 3-((3 aR,6 aS)-5-(4-(4-amino-3-(4-phen oxy ph eny1)-1H- pyrazolo [3 ,4-d]pyrim idin-1 -yl)piperidi n-l-yl)hexahydrocyclopenta[c]pyrrol-2(1I1)-y1)azetidine-1-carboxylate (59a) NN¨Boc N¨/
The above crude product 1-(1-43aR,6aS)-octahydrocyclopenta[c]pyrrol-5-yppiperidin-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo [3 ,4-d]pyrimidi n-4-amine trifluoroacetate (52b) (270 mg) was dissolved in 6 mL of DCE, and 1-Boc-3-io azetidinone (188 mg, 1.10 mmol), glacial acetic acid (0.08 mL) and anhydrous sodium sulphate (400 mg) were successively added at room temperature, the mixture was stirred for 30 min, then sodium triacetoxyborohydride (400 mg, 1.89 mmol) was added, and the mixture was stirred at room temperature for 16 h. To the reaction solution was added 50 mL of water, the p1-1 of the aqueous phase was adjusted to 10 15 with 2 mol/L sodium hydroxide aqueous solution, and the resulted solution was extracted with dichloromethane (30 niL X 3). The organic phase was combined, washed with water (20 mL x 2), dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 10 : 1-8 :
20 1), to obtain tert-butyl 3-((3aR,6aS)-5-(4-(4-amino-3-(4-phenoxyphenyI)-Date Recue/Date Received 2021-09-09 pyrazolo[3,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)hexahy drocyclopenta[c]pyrrol e-2(1H)-yl)azetidine- 1 -carboxylate (59a) (265 mg, two-step yield calculated from compound 52a: 96%).
LCMS m/z = 651.4 [1\4+ Tr Step 2:
1 1 -43 aR,6aS)-2-(azetid in-3-y1) octahydrocyc lopenta[clpyrrol -5-y1 )piperid n-4-y1)-3 -(4-phenoxypheny1)-1H-pyrazolo [3,4-d] pyrimidin-4-amine (59b) H NH
N, N
\ N

Tert-butyl 34(3aR,6aS )-5-(4-(4-amino-3-(4-phenoxypheny1)- 1H-pyrazo10 [3,4-d]pyrim idin-1 -y1)piperidin-1-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-y1)azetidine-1-carboxylate (59a) (210 mg, 0.32 mmol) was dissolved in 2 mL of dichloromethane, and I mL of tritltioroacetic acid was added, the mixture was reacted at room temperature for 2.5 h. The pH of the reaction solution was adjusted to 10 with 2 mol/L
sodium hydroxide aqueous solution, and the aqueous phase was extracted with dichloromethane (10 mL x 3). The organic phase was combined, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, to obtain the crude product 1-(1- ((3 aR,6aS)-2- (azeti din-3-y1 )hexahy drocyc lopenta[c]pyrrol -5-y 1)piperidi n-4-y1)-3-(4-phenoxypheny1)-1 H-pyrazo lo [3 ,4-d] pyri m idi n-4-amine (59b) (165 mg).
LCMS m/z = 551.4 [M 1] .
Step 3:
5434(3 aR,6aS )-5-(4-(4-amino-3-(4-phenoxypheny1)-1H -pyrazolo [3 ,4 -d]pyrimidin- 1-yl)piperidin-l-yl)hexahydrocyclopenta[c]pytTo1-2( I H)-y Dazetidin- 1 -y1)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (compound 59) Date Recue/Date Received 2021-09-09 N

N
\ H2N N
The above crude product 1-(14(3aR,6aS)-2-(azetidin-3-yl)hexahydrocyclopenta[c]pyrrol-5-yOpiperidin-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (59b) (165 mg) was dissolved in 5 mL of DMSO, and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO

for the synthetic method) (82 mg, 0.30 mmol) and diisopropylethylamine (194 mg, 1.50 mmol) were added at room temperature, the mixture was warmed to 80 C and reacted for 4 h. The reaction solution was cooled to room temperature, then poured into 20 mL of water, and the aqueous phase was extracted with the mixed solvent of dichloromethane/methanol (v/v) =10 : 1 (30 mL x 3). The organic phase was combined, washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichlorornethane/methanol (v/v) = 15 :
1-8 :
1), to obtain 5 -(3-((3aR,6aS)-5 -(4-(4-amino-3-(4 -pherioxypheny1)-1 H-pyrazolo [3 ,4 -d]pyrim idin-1 -yl)piperidin-1 -yl)hexahy drocyclopenta[c]pyrrol-2 (11-1)-azetidin-l-y1)-2-(2,6-dioxopiperidin-3-yl)isoindol inc-1,3-dione (compound 59) (108 mg, two-step yield calculated from compound 59a: 42%).
1H NMR (400 MHz, CDCI3) 8.36 (s, 1H), 8.13 (s, 1H), 7.68- 7.58 (m, 3H), 7.43 - 7.33 (m, 2H), 7.22 - 7.02 (m, 511), 6.77 (d, 111), 6.50 (dd, 1H), 5.43 (br.s, 211), 4.93 (dd, 111), 4.82 - 4.68 (in, HT), 4.11 - 4.03 (m, 2H), 3.94 - 3.83 (m, 211), 3.51 -3.42 (m, 1H), 3.23 - 3.11 (m, 2H), 2.94 - 2.63 (n, 4H), 2.62 - 2.30 (m, 8H), 2.28 -2.16 (in, 311), 2.16- 2.08 (m, 1H), 2.06- 1.95 (m, 2H), 1.44- 1.22 (m, 311).
LCMS m/z = 807.4 [M-4-1]'.
Example 60:
5-(3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-d]pyrimidin- 1-yl)piperi di n- 1-y1)-[ 1,3 ' : 1',3"-terazetidin]- 1"-y1)-2-(2,6- dioxopi peri din-3-Aisoindoline-1,3-dione (compound 60) Date Recue/Date Received 2021-09-09 PN
/ \ H2N N
N---r-/
Q Q
___CfN1 14 __CN
0 1p )H2N N Fi2N4rlN
17d 60a N
----'N- ----1-1''N
H2 N / \ N
N=1 H2N / \ N Cornix)bnd 60 rsl¨i 60b Step 1:
tert-butyl 3-(4-(4-amino-3 -(4-ph enoxypheny1)-1H -pyrazolo [3,4-d]pyri midin-yl)piperidin-l-y1)-[1,31: 1 ',3"-terazetidine]-1"-carboxylate (60a) Q 7.--N-Floe ___N----'---,r;N-----/

N, _CIN
--- N-/
H2N "N
N=I
I --[ 111 -(azetidin-3-yl)a7etidin-3-y1]-4-piperidy1]-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine (17d) (496 mg, 1.00 mmol) was dissolved in 10 mL of DCE, and 1-Boc-3-azetidinone (342 mg, 2.00 mmol), glacial acetic acid (0.15 mL) and anhydrous sodium sulphate (800 mg) were successively added at room temperature, the mixture was stirred at room temperature for 30 min, then sodium triacetoxyborohydride (726 mg, 3.43 mmol) was added, and the mixture was stirred at room temperature for 16 h. To the reaction solution was added 50 mL
of water, the pH of the aqueous phase was adjusted to 10 with 2 N sodium hydroxide as aqueous solution, and the resulted solution was extracted with dichloromethane (30 mL x 3). The organic phase was combined, washed with water (20 mL x 2), dried Date Recue/Date Received 2021-09-09 over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) ¨ 10 : 1-8 : 1), to obtain tert-butyl 3-(4-(4-amino-3 -(4-phenoxypheny1)-1H-pyrazolo [3,4-d[pyri midin-l-yl)piperidin-l-y1)-[1,3':
1`,3 "-terazetidine]-1"-carboxylate (60a) (521 mg, yield: 80%).
LCMS m/z ¨ 652.5 [M+1]' .
Step 2:
1-(1-([1,3':1',3"-terazetidin]-3-y1)piperidin-4-y1)-3-(4-phenoxypheny1)-11-1-pyrazolo[3,4-d]pyrimidin-4-amine (60b) =
CIN
N-/ \ N H2N
N
Tert-butyl 3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-l-y1)piperidin-1-y1)41,3`:1',3"-terazetidinel-1"-carboxylate (60a) (143 mg, 0.22 mmol) was dissolved in 4 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added, the mixture was reacted at room temperature for 1.5 h. The p1-1 of the as reaction solution was adjusted to 10 with 2 mol/L sodium hydroxide aqueous solution, and the aqueous phase was extracted with dichloromethane (10 mL x 3). The organic phase was combined, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, to obtain the crude product 1-(1-([1,3': P,3"-terazetidin]-3 -yl)piperidin-4-y1)-3 -(4-phenoxypheny1)-1H-pyrazolo [3 ,4 -d[pyrimidin -4-amine (60b) (113 mg).
LCMS in/z = 552.4 [M+1] .
Step 3:
5-(3-(4-(4-am ino-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-d]pyri m i di n-1-yl)piperidin-l-y1)-[1,3': 1',3"-terazetidin]-1"-y1)-2-(2,6-dioxopiperidin-3-ypisoindoline-1,3-dione (compound 60) Date Recue/Date Received 2021-09-09 N
,N, ¨ 0 H

The above crude product 1-(1-( [1,3': I ',3"-terazetidi n]-3-yl)piperidin-4-y1)-3-(4-phenoxypheny1)-11-1-pyrazolo[3,4-d]pyrimidin-4-amine (60b) (113 mg) was dissolved in 5 mL of DMSO, and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (55 mg, 0.20 mmol) and diisopropylethylamine (129 mg, 1.00 mmol) were added at room temperature, the mixture was warmed to 80 C and reacted for 3.5 h. The reaction solution was cooled to room temperature, then poured into 20 mL of water, and the aqueous phase was extracted with the mixed solvent of dichloromethane/methanol (v/v) =10: 1(30 MI_ x 3). The organic phase was combined, washed with 40 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) ¨ 15 : 1-8 : 1), to obtain 5-(3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazo lo [3 ,4-djpyrimidin-1-y1)piperidi n-1 -yI)-[1,3 1',3"-Is terazetidin]-1"-y1)-2 -(2 ,6-dioxopiperidi n-3 -yl)i soindoline-1 ,3 -di one (compound 60) (99 mg, two-step yield calculated from compound 60a: 56%).
NMR (400 MHz, CDCI3) 6 8.37 (s, 1H), 7.68 - 7.59 (m, 3H), 7.43 - 7.35 (m, 2H), 7.21 -7.11 (m, 3H), 7.11 - 7.05 (m, 2H), 6.76 (d, 1H), 6.49 (dd, 1H), 5.72 (br.s, 21-1), 4.96 - 4,87 (m, 114), 4.84 - 4.70 (m, 1H), 4.08 - 3.96 (m, 2H), 3.88 -3.78 (m, 2H), 3.69 - 3.60 (m, 1H), 3.60 - 3.51 (in, 2H), 3.44 - 3.32 (in, 3H), 3.18 -2.96 (m, 5H), 2.96 -2.64 (m, 5H), 2.50 - 2.33 (m, 2H), 2.16- 1.97 (m, 5H).
LCMS m/z = 808.4 [M+1].
Example 61:
54 (3 aR,6aS)-5-(3-(4-(4- amino-3-(4-phenoxypheny1)-1H-pyrazolo [3,4-d]pyrimidin-l-yl)piperidin-l-y1)azetidin-l-yOhexahydrocyclopenta[c]pyrrol-2(1H)-y1)-2-(2,6-dioxopiperidin-3-ypisoindoline-1,3-dione (compound 61) Date Recue/Date Received 2021-09-09 o N
. 'N
H2N)' N

,N_ /.....nl-Boc __`
CI- IP ,P4'N-0 -I sic" 0 410 , --1,/ 'NA Step2 N, .-_krNH
H2N) 'N H2N N
17b 613 -, - WISP41-4 111/
H --wir:,:VIN N. I NI__10 ONH---C/
Step 3 N=4 / \ N H2N
61b N=/ Compound 61 Step 1:
tert-butyl (3aR,6a S)-5 -(3-(4-(4-am ino-3-(4-phenoxyph eny1)-1H-pyrazolo [3 ,4-s d]pyrimidin-l-yl)piperidin-l-yl)azetidin-1-yphexahydrocyclopenta [c]pyiTole-2(1H)-carboxylate (6 I a) N, ---C/
H
H2N / \N
N-141-(azetidin-3-y1)-4-piperidy11-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine (17b) (650 mg, 1.47 mmol) was dissolved in 12 mL of DCE, and tert-butyl (3aR,6aS)-5-oxo hexahydrocyclopenta[cipyrrol-2(1H)-carboxylate (451 mg, 2.00 mmol), glacial acetic acid (0.14 mL) and anhydrous sodium sulphate (700 mg) were successively added at room temperature, the mixture was stirred at room temperature for 30 min, then sodium triacetoxyborohydride (636 mg, 3.00 mmol) was added, and the mixture was stirred at room temperature for 16 h. To the reaction solution was added 50 mL of water, the pH of the aqueous phase was Date Recue/Date Received 2021-09-09 adjusted to 10 with 2 mol/L sodium hydroxide aqueous solution, and the resulted solution was extracted with dichloromethane (30 mL x 3). The organic phase was combined, washed with water (20 mL x 2), dried over anhydrous sodium sulphate, and concentrated. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 10: 1-8 : 1), to obtain tert-butyl (3aR,6aS)-5-(3-(4-(4-amin o-3-(4-plienoxyplieny1)-1H -pyrazolo [3,4-d] pyri mid in -1-yl)piperidin- 1-yl)azetidin- 1-yl)hexahydrocyc lopenta[ c]pyrrol-2(1H)-carboxylate (61a) (310 mg, yield: 32%).
LCMS m/z = 651.4 [M 1].
Step 2:
1-(1-((3 aR,6aS )-2-(azetidin-3-y1) octahydrocyc lopenta [c]pyrrol-5-yl)piperidi n-4-yI)-3 -(4-phenoxypheny1)-1H-pyrazolo [3,4-d] pyrirnidin-4-am inc (61b) NZj N
H2N \ N
Tert-butyl (3aR,6aS)-.5 -(3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo [3 ,4-d]pyrimidin-l-yl)piperidin-l-yl)azetidin-l-y1)hexahydrocyclopenta[c]pyrrol-2(111)-carboxylate (61a) (310 mg, 0.48 mmol) was dissolved in 3 mL of dichloromethane, and 2 int of trifluoroacetic acid was added, the mixture was reacted at room temperature for 2.5 h. The pH of the reaction solution was adjusted to 10 with 2 mol/L
sodium hydroxide aqueous solution, and the aqueous phase was extracted with dichloromethane (10 mL x 3). The organic phase was combined, dried over anhydrous sodium sulphate, and concentrated, to obtain the crude product 141-((3 aR,6aS)-2 -(azeti din-3 -yl)octahydrocycl openta[c]pyrrol -5-yl)piperi din-4-y1)-3 -(4-phenoxypheny1)-1H-pyrazolo[3 ,4-d]pyrim idin-4-am ine (61b) (255 mg).
LCMS in/z = 551.4 [M+1]
Step 3:
54(3aR,6aS)-5-(3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrim idin- 1-yl)p iperidin -1-y 1)azetidin -1-yphexahydrocyclopenta [c]pyrrol-2 (1H)-Date Recue/Date Received 2021-09-09 y1)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (compound 61) I / NJ

N¨/
The above crude product 1 -( 1-((3aR,6aS)-2-(azetidin-3-yl)octahydrocyclopenta [c] pyrrol-5-yl)piperid in-4-y1)-3 -(4 -phenoxypheny1)-pyrazolo[3,4-d]pyrimidin-4-amine (61b) (200 mg) was dissolved in 8 mL of DMSO, and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO

for the synthetic method) (99 mg, 0.36 mmol) and diisopropylethylamine (233 mg, 1.80 mmol) were added at room temperature, the mixture was warmed to 80 C and reacted for 4 h. The reaction solution was cooled to room temperature, then poured into 20 mL of water, and the aqueous phase was extracted with the mixed solvent of dichloromethane/methanol (v/v) =10 : 1 (30 mL x 3). The organic phase was combined, washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) =
15:
1-8 : 1), to obtain 54(3aR,6aS)-5-(3-(4-(4-amino-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-1-y1)piperidin-1-y1)azetidin-1-yphexahydrocyclopenta[e]pyrro1-2(1H)-y1)-2-(2,6-dioxopiperidin-3-y1 )isoindoline-1,3-dione (compound 61) (148 mg, two-step yield calculated from compound 61a:
49%).
1H NMR (400 MHz, CDC13) 6 8.52 (br.s, 1H), 8.37 (s, 1H), 7.69 - 7.60 (m, 3H), 7.44- 7.34 (m, 211), 7.24 -7.02 (m, 511), 6.96 (d, 111), 6.67 (dd, 111), 5.48 (br.s, 211), 4.92 (dd, 1H), 4.83 - 4.70 (m, 1H), 3.70 - 3.43 (m, 4H), 3.42 - 3.30 (m, 2H), 3.10 -2.65 (m, 10H), 2.49 -2.32 (m, 2H), 2.16- 1.94 (m, 6H), 1.52- 1.20 (m, 411).
LCMS m/z = 807.4 [M+
Example 62:
5-(2-(3-(4-(4-am ino-3-(4-ph enoxyph eny1)- 1H -pyrazo lo [3 ,4-d]pyrim idin -yppiperidin-1 -yl)azeti din-1-y1)-7- azaspiro [3.5 ]nonan-7-y1)-2-(2 ,6-dioxop iperi din-3-Date Recue/Date Received 2021-09-09 yl)isoindoline-1,3-dione (compound 62) N-, N
H2N 'N
N Bac Stup2 ) N _CIN- Slept 0 ./
H2N _____________ N H2N \N
N=1 17b 62a N (.2 . N
St.p 3 0 \ N F-Ã2N
62b 112N):
N=". Compound 62 Step 1:
tert-butyl 2-(3-(4-(4-amino-3-(4-phenoxypheny1)-1 H-pyrazo lo [3,4-d]pyrimidin-l-Apiperidin-l-ypazetidin-1-y1)-7-azaspiro [3.51n0nane-7-earboxylate (62a) N
H2N \N
N=/
141-(azetidin-3-y1)-4-piperidylj-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-amine (17b) (650 mg, 1.47 mmol) was dissolved in 12 mL of DCE, and tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-earboxylate (479 mg, 2.00 mmol), glacial acetic acid (0.14 mL) and anhydrous sodium sulphate (700 mg) were successively added at room temperature, the mixture was stirred at room temperature for 30 min, then sodium triacetoxyborohydride (636 mg, 3.00 mmol) was added, and the mixture was stirred at room temperature for 16 h. To the reaction solution was Date Recue/Date Received 2021-09-09 added 50 mL of water, the pH of the aqueous phase was adjusted to 10 with 2 mol/L
sodium hydroxide aqueous solution, and the resulted solution was extracted with dichloromethane (30 mL x 3). The organic phase was combined, washed with water (20 mL x 2), dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) ¨ 10 : 1-8 : 1), to obtain tert-butyl 243 -(4- (4-amino-3 44-phenoxypheny1)-1H-pyrazolo [3 ,4-djpyrimidin-1-yl)piperidin-1 -yl)azeti din-1 -yI)-7-azaspiro[3 .5] nonanc-7-carboxylate (62a) (404 mg, yield: 41%).
LCMS m/z = 665.4 [M+1] .
Step 2:
14 1-(1-(7-azaspiro[3.5]nonan-2-yl)azetidin-3-yppiperidin-4-y1)-344-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (62b) H2N \ N
N=7 Tert-butyl 2434444-amino-3 -(4-phenoxypheny1)-1H-pyrazolo[3 ,4-d]pyrimidin-1 -yl)piperidi n-l-yl)azeti din-l-y1)-7-azaspiro [3 .5] nonane-7-c arboxylate (62a) (200 mg, 0.30 mmol) was dissolved in 2 mL of dichloromethane, and 1 inL
of trifluoroacetic acid was added, the mixture was reacted at room temperature for 2 h.
The pll of the reaction solution was adjusted to 10 with 2 mol/L sodium hydroxide aqueous solution, and the aqueous phase was extracted with dichloromethane (10 mL
x 3). The organic phase was combined, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, to obtain the crude product 1414147-azaspiro[3.5]nonan-2-y Dazetidin-3-yl)piperidin-4-y1)-344-phenoxypheny1)-1H
pyrazolo[3,4-d] pyrimid in-4-amine (62b) (161 mg).
LCMS m/z = 565.4 [M+1r.
Step 3:
5-(24344(4-amino-344-phenoxypheny1)- I H -pyrazo lo [3 ,4-d]pyrim idin - I -Date Recue/Date Received 2021-09-09 yl)piperidin- 1 -y1)azeti din- 1 -yI)-7-azaspiro [3 .5jnonan-7-yI)-2-(2 ,6-dioxop iperid in-3-yl)isoindoline-1,3-dione (compound 62) o p0 ----7-1\-0 ...,),.

The above crude product 1-(1-(1-(7-azaspiro[3.5jnonan-2-y1)azetidin-3-yl)piperidin-4-y1)-3-(4-phenoxypheny1)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (62b) (161 mg) was dissolved in 6 mL of DMSO, and 2-(2,6-dioxopiperidin-3-y1)-5-fluoroisoindoline-1,3-dione (see WO 2017197056 for the synthetic method) (80 mg, 0.29 nunol) and diisopropylethylamine (188 mg, 1.45 inniol) were added at room temperature, the mixture was warmed to 80 C and reacted for 4 h. The reaction solution was cooled to room temperature, then poured into 20 mL of water, and the aqueous phase was extracted with the mixed solvent of diehloromethane/methanol (v/v) =10: 1 (30 mL x 3). The organic phase was combined, washed with 50 mL of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure, then the crude product was separated and purified by silica gel column Is chromatography (dichloromethane/methanol (v/v) = 15 : 1-8 : 1), to obtain 54243-(4-(4-amino-3-(4-phen oxypheny1)- I H-pyrazolo[3,4-d]pyri midin- 1-yl)piperidin-1-yl)azctidin- 1-y1)-7-azaspiro[3 .5 ]nonan-7-y1)-2-(2,6-dioxopiperidin-3-y 1)i soin dol inc-I,3-di one (compound 62) (128 mg, two-step yield calculated from compound 62a:

52%).
1H NMR (400 MHz, CDC13) 6 10.34 (br.s, 1H), 8.39 (s, 1H), 7.70- 7.60 (m, 3H), 7.43 - 7.33 (m, 2H), 7.27 - 7.24 (in, 1H), 7.20 - 6.99 (m, 6H), 5.82 (br.s, 2H), 5.00 -4.89 (in, I H), 4.85 - 4.71 (m, 1H), 3.67 - 3.51 (in, 2H), 3.46 - 3.21 (m, 5H), 3.16 -2.66 (m, 8H), 2.50 -2.33 (m, 2H), 2.20- 1.92 (m, 7H), 1.87- 1.61 (m, 6H).
LCMS in/z = 821.4 [M+1]'.
Test example 1. Experiment on inhibiting cell proliferation Date Recue/Date Received 2021-09-09 SU-DHL-4, Mino, and SU-DHL-6 cells, in the culture medium of RPMI1640+10% FBS, were cultured in an incubator at 37 C under 5% CO2. Cells were plated in a 96-well plate. Specifically, SU-DHL-4 cells were at 20000/well, Mino and SU-DHL-6 cells were at 5000/well, with 90 pt/well. 10 pL of the compounds at different concentrations were added to each well. There were 3 replicate wells for each concentration, and the last column, added with DMSO, was used as a vehicle control group. The cultures were continued for 72 hours at under 5% CO2. After 72 hours, 100 1.1L of detection reagent (Cell Viability Assay, Promega, G7573) was added to each well, and the cultures were uniformly mixed for 2 minutes, and incubated at room temperature for 10 minutes. The fluorescence signal value was measured with a microplate reader (PHERAstar FSX). The 1050 value of the compound on cell proliferation inhibition was calculated using Origin 9.2 software, and the inhibition rate at the highest concentration of the compound (Max inhi. %) was calculated according to formula (1).
Max inhi. % = (1-T72 administration/T72 vehicle) x100 Formula (1).
OCI-LY10 and TMD-8 cells, in the culture medium of RPMI1640+10% FBS, were cultured in an incubator at 37 C under 5% CO2. Cells were plated in a 96-well plate. Specifically, OCI-LY10 cells were at 10000/well, and TMD-8 cells were at 8000/well, with 90 pt/well. These cells were cultured at 37 C under 5% CO2 overnight. On the next day, 10 pL of the compounds at different concentrations were added to each well. There were 3 replicate wells for each concentration, and the last column, added with DMSO, was used as a vehicle control group. The cultures were continued for 72 hours at 37 C under 5% CO2. After 72 hours, 50 JAL of detection reagent (Cell Viability Assay, Promega, G7573) was added to each well, and the cultures were uniformly mixed for 2 minutes, and incubated at room temperature for 10 minutes. The fluorescence signal value was measured with an Envision2104 plate reader (PerkinElmer). The inhibition rate was calculated using formula (2), wherein RLU compound was the readout of the drug treated group, RLU control was the average value of the vehicle control group, and RLU blank was the average value of the cell-free wells. The 1050 value was calculated using GraphPad Prism software.
IR (%) = ( I -(RLU compound-RLU blank)/(RLU controi-RLU biank))*100%
formula (2) Date Recue/Date Received 2021-09-09 The results for 1050 values on proliferation inhibition of Mino cells were shown in Table 1.
Table 1 1050 value on proliferation inhibition of Mino cells Serial No. Compound No. 1C5g (nM) 1 P131* 844 2 " Compound 2 633 3 Compound 6 421 4 Compound 8 309 Compound 9 367 6 Compound 10 405 7 Compound H 114 t 8 Compound 12 183 __ _ - 9 Compound 13 677 Compound 17 20 11 Compound 17-a 8.0 12 Compound 17-b 7.2

13 ' Compound 18-1 " 18

14 Compound 19 48 Compound 20-1 " 32 16 Compound 23 295 17 Compound 24 629 18 Compound 25 282 19 Compound 27 503 Compound 32 188 21 Compound 38 81 22 Compound 39 41 23 Compound 40 7.3 24 Compound 41 10.3 Compound 42 15 26 Compound 43 __ H 10 27 Compound 44 ' 15 28 Compound 45 9.6 29 Compound 46-1 27 Compound 49-1 113 31 Compound 49-2 10 Date Recue/Date Received 2021-09-09 32 Compound 50 112 33 Compound 54 200 34 Compound 59 501 35 Compound 60 165 36 Compound 61 100 37 Compound 62 38 *Notes: denoting a trifluoroacetate thereof.
The results for Max inhi. % values on proliferation inhibition of Mino cells were shown in Table 1-1.
Table 1 -1. Max inhi. A value on proliferation inhibition of Mino cells Serial Compound No. Mino Max inhi. %
No.
1 Compound 15 99.8 2 Compound 16 99.7 3 Compound 26 74.3 4 Compound 29 71.2 Compound 30 82.5 6 Compound 31 78.3 7 Compound 48 95.7 8 Compound 51 99.7 9 Compound 52 99.7 Compound 53 99.6 11 Compound 55 99.9 12 Compound 56 99.9 13 Compound 57 99.2 14 Compound 58 95.3 5 The results for IC50 values on proliferation inhibition of SU-DHL-4 cells were shown in Table 2.
Table 2 IC50 value on inhibition of SU-DHL-4 cells Serial Compound No. IC50 (nM) No.
1 P131* 1184 2 Compound 2 41 3 Compound 8 255 Date Recue/Date Received 2021-09-09 4 Compound 9 295 5 Compound 11 189 6 Compound 12 56 7 Compound 13 70 8 Compound 14 60 9 Compound 17 367 10 Compound 17-a 481 11 Compound 17-b 460 12 Compound 18-1 20 13 Compound 19-1 394 14 Compound 32 330

15 Compound 37 631

16 Compound 38 469

17 Compound 40 74

18 Compound 41 329

19 Compound 42 382

20 Compound 43 330

21 Compound 45 110 *Notes: denoting a trifluoroacetate thereof.
The results for Max inhi. % values on proliferation inhibition of SU-DHL-4 cells were shown in Table 2-1.
Table 2-1. Max inhi. % value on proliferation inhibition of SU-DHL-4 cells Serial SU-DIIL-4 Max inhi. %
Compound No.
No.
Compound 34-a 94.4 2 Compound 34-b 99.2 3 Compound 36-a 99.6 4 Compound 36-b 99.8 The results for 1050 values on proliferation inhibition of SU-DHL-6 cells were shown in Table 2-2.
Table 2-2 IC50 value on inhibition of SU-DHL-6 cells Serial Compound No. IC50 (nM) No.
1 P131* 1638 Date Recue/Date Received 2021-09-09 2 Compound 2 26 3 Compound 6 166 4 Compound 8 399 Compound 9 155 6 Compound 10 77 7 Compound 11 109 8 Compound 12 106 9 C- ompound 14 86 Compound 17 744 11 Compound 17-a 524 12 Compound 17-b 662 13 - Compound 18-1 29 14 Compound 19 782 C- ompound 32 393 16 Compound 38 888 17 Compound 40 54 18 Compound 41 670 19 Compound 42 177 Compound 43 407 - 21 Compound 45 125 *Notes: denoting a trifluoroacetate thereof.
The results for IC50 values on proliferation inhibition of OCI-LY10 cells were shown in Table 2-3.
Table 2-3 IC50 value on inhibition of OCI-LYI 0 cells Scrial Compound No. 1C5u (nM) No.
1 P131* 29 2 Compound 8 3 3 C- ompound 17 5 4 Compound 18-1 4 5 Compound 19-1 23 6 Compound 40 3 7 Compound 42 3 8 C- ompound 45 3 5 *Notes: denoting a trifluoroacetate thereof.
Date Recue/Date Received 2021-09-09 The results for IC50 values on proliferation inhibition of TMD-8 cells were shown in Table 2-4.
Table 2-4 IC50 value on inhibition of TMD-8 cells Serial Compound No. 1050 (nM) No.
1 P131* 104 2 Compound 8 22 3 Compound 17 22 4 Compound 18-1 8 Compound 19-1 14 6 Compound 40 12 7 Compound 42 16 8 Compound 45 16 *Notes: denoting a trifluoroacetate thereof.
5 Conclusion: The compounds synthesized by using the technique of the present invention have a significant inhibitory effect on the proliferation of SU-DHL-4 cells and SU-DHL-6 cells (human B lymphoma cells), Mino cells (mantle cell lymphoma cells), and OCI-LY I 0 cells (diffuse large B cell lymphoma cells) and TMD-8 cells (human diffuse large B lymphoma cells).
2. Pharmaeakinetie experiment in rats Objective: In this experiment, a single dose of each test compound was administered to SD rats intravenously and intragastrically, the concentrations of the test compound in plasma of rats were measured, and the pharmacokinetic characteristics and bioavailability of the test compound in rats were evaluated.
Experimental animals: Male SD rats, 200-250 g, 6-8 weeks old, 6 rats/test compound. The experimental animals were purchased from CHENCiDU DOSSY
EXPERIMENTAL ANIMALS CO., LTD.
Experimental method: On the day of the experiment, 6 SD rats were randomly grouped according to their body weight. The animals were fasted with water available for 12 to 14 hours one day before the administration of a test compound, and were fed 4 hours after the administration. The administration information was shown in Table 3.
Date Recue/Date Received 2021-09-09 Table 3 No.
of Administration information rats Administ Group Adminis Admini Colle Mode ration Test tration stration cted of Male concentr Vehicle compound dosage* volume samp adminis ation (mg/kg) (mL/kg) les tration (mWmL) Compound 5% DMSO +
of the Plas Intrave GI 3 5 1 5 5% Solutol +
present ma nously 90% Saline invention Compound of the Plas lntragas G2 3 20 2 10 0.5u/0 MC
present ma trically invention *Dosage is calculated based on free base.
Sampling: Before and after the administration, 0.1 ml of blood was taken from the orbit of the rats under isoflurane anesthesia, and placed in an EDTAK2 centrifuge tube. Centrifugation was carried out at 5000 rpm at 4 C for 10 min and the plasma was collected.
Time points for plasma collection in G1 group: 0, 5 min, 15 min, 30 min, 1 h, Ii, 4 h, 6 1-1, 8 h, and 24 h.
Time points for plasma collection in G2 group: 0, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 b.
Before analysis and detection, all samples were stored at -80 C. The samples were analysed quantitatively by LC-MS/MS. The results were shown in Table 4.
Table 4 The pharmacokinetie parameters of compounds in plasma of rats Mode of Test compounds AUCO.t (ng/m1=11) F (%) administration*
P131¨ i.g. (20 mg/kg) Compound 1 i.g. (20 mg/kg) 479 + 197 N/A
Date Recue/Date Received 2021-09-09 Compound 2 i.g. (20 mg/kg) 18.6 + 2.8 N/A
Compound 3 i.g. (20 mg/kg) 211 + 46 N/A
Compound 4 i.g. (20 mg/kg) 36.0+ 10 N/A
=
Compound 5 i.g. (20 mg/kg) 81.7 68 N/A
Compound 6 i.g. (20 mg/kg) 328 41 N/A
Compound 7 i.g. (20 mg/kg) 105 + 54 N/A
Compound 8 i.g. (20 mg/kg) 634 1 238 11.8 1 4.4 Compound 9 i.g. (20 mg/kg) 8.93 4.3 N/A
Compound 17 i.g. (20 mg/kg) 2344 274 6.57 1 0.77 Compound 18-1 i.g. (20 mg/kg) 218 68 N/A
Compound 19-1 i.g. (20 mg/kg) 1263 117 N/A
Compound 20-1 i.g. (20 mg/kg) 891 1 164 N/A
Compound 21 i.g. (20 mg/kg) 3205 973 12.4 3.8 Compound 32 i.g. (20 mg/kg) 322 64 N/A
Compound 37 i.g,. (20 mg/kg) 473 105 N/A
Compound 49-2 i.g,. (20 mg/kg) 475 237 4.14 2.1 *Notes: i.g. (intragastrically) administration of the compounds.
**Notes: denoting a trifluoroacetate thereof;
Notes: The concentration at each detection point was lower than the lower limit of quantification by 0.5 ng/mL.
Conclusion: The compounds synthesized by using the technique of the present invention had a certain oral bioavailability in rats.
3. Pharmacokinetic experiment in mice Objective: In this experiment, a single dose of each test compound was administered to ICR mice intravenously and intragastrically, the concentrations of the test compound in plasma of mice were measured, and the pharmacokinetic characteristics and bioavailability of the test compound in mice were evaluated.
Experimental animals: Male ICR mice, 20-25 g, 6-8 weeks old, 24 mice/compound. The experimental animals were purchased from CHENGDU
DOSSY EXPERIMENTAL ANIMALS CO., LTD.
Date Recue/Date Received 2021-09-09 Experimental method: On the day of the experiment, 24 1CR mice were randomly grouped according to their body weight. The animals were fasted with water available for 12 to 14 hours one day before the administration of a test compound, and were fed 4 hours after the administration. The administration information was shown in Table 5.
Table 5 No.
of Administration information mice Administr Group Adminis Adminis Mode ation Test tration tration Collected of Male co nce ntra t Vehicle compound dosage* volume samples ad minist ion (mg/kg) (mL/kg) ration (mg/mL) Compound 5% DMSO
of the Introvert =
5%
G1 9 5 1 5 Plasma present ously Solutol invention =
90% Saline Oral Compound G2 15 10 1 10 Plasma (intragas 0.5% MC
Compound trically) =
*Dosage is calculated based on free base;
Sampling: Before and after the administration, 0.06 ml of blood was taken from the orbit of the mice under isoflurane anesthesia, and placed in an EDTAK2 centrifuge tube. Centrifugation was carried out at 5000 rpm at 4 C for 10 min and the plasma was collected.
Time points for plasma collection in G1 group: 0, 5 min, 15 min, 30 min, 1 h, h, 4 h, 6 h, 8 h, and 24 h;
Time points for plasma collection in G2 group: 0, 15 min, 30 min, 1 h, 2 h, 4 h, is 6 h, 8 h, and 24 h;
Before analysis and detection, all samples were stored at -80 C. The samples were analysed quantitatively by LC-MS/MS. The results were shown in Table 6.
Table 6 The pharmacokinetie parameters of test compounds in mice Date Recue/Date Received 2021-09-09 Mode of Test compounds AUCO-t (ng/ml=h) F (%) administration*
Compound 17 i.g. (10 mg/kg) 2426 10.8 *Notes: i.g. (intragastrically) administration of the compounds.
Conclusion: The compounds synthesized by using the technique of the present invention had a certain oral bioavailability in mice.
4. Pharmacokinetic experiment in rats Objective: In this experiment, a single dose of each test compound was administered to SD rats intravenously and intragastrically, the concentrations of the test compound in plasma of rats were measured, and the phannacokinetic characteristics and bioavailability of the test compound in rats were evaluated.
Experimental animals: Male SD rats, 200-250 g, 6-8 weeks old, 6 rats/compound. The experimental animals were purchased from CHENGDU DOSSY
EXPERIMENTAL ANIMALS CO., LTD.
Experimental method: On the day of the experiment, 6 SD rats were randomly grouped according to their body weight. The animals were fasted with water available for 12 to 14 hours one day before the administration of a test compound, and were is fed 4 hours after the administration. The administration information was shown in Table 7.
Table 7 No.
of Administration information rats Administr Group Adminis Adminis Mode ation Test tration tration Collected of Male concentrat.
Vehicle compound dosage* volume samples administ ion (mg/kg) (mt./kg) ration (mg/m L) 5%
Compound Intraven DMSO
G1 3 5 1 5 Plasma Compound ously 5%
Solutol Date Recue/Date Received 2021-09-09 90%
Saline 5%
DMSO +
.5%
Oral Solutol Compound G2 3 20 2 10 Plasma (intragas +
30%
Compound trically) + 60%
(20%S13E-p-CD) *Dosage is calculated based on free base.
Sampling: Before and after the administration, 0.1 mL of blood was taken from the orbit of the rats under isoflurane anesthesia, and placed in an EDTAK2 centrifuge tube. Centrifugation was carried out at 5000 rpm at 4 C for 10 min and the plasma was collected.
Time points for plasma collection in G1 group: 0, 5 min, 15 min, 30 min, 1 h, 11, 4 h, 611, 811, and 24 h.
Time points for plasma collection in 62 group: 0, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h.
Before analysis and detection, all samples were stored at -80 C. The samples were analysed quantitatively by LC-MS/MS. The results were shown in Table 8.
Table 8 The pharmacokinetic parameters of compounds in plasma of rats Mode of Test compounds AUC04 (ng/ml-h) F (%) administration*
Lg. (20 mg/kg) Compound 38 i.g. (20 mg/kg) 7257 2863 13.3 1 5.2 Compound 39 i.g. (20 mg/kg) 2831 474 9.1 _+_ 1.5 Compound 40 i.g. (20 mg/kg) 5419 1263 17.41 4.0 Compound 41 i.g. (20 mg/kg) 79061 1099 10.8 1 1.5 Compound 42 i.g. (20 mg/kg) 11951 327 9.14 -1 2.5 Compound 43 i.g. (20 mg/kg) 4495 _L 886 11.0 1 2.2 Compound 44 i.g. (20 mg/kg) 877 _L 98 5.73 1 0.64 Date Recue/Date Received 2021-09-09 Compound 45 i.g. (20 mg/kg) 3437 1491 19.7 8.5 *Notes: i.g. (intragastrically) administration of the compounds;
"Notes: Free form;
'Notes: The concentration at each detection point was lower than the lower limit of quantification by 0.5 ng/mL.
Conclusion: The compounds synthesized by using the technique of the present invention had a certain oral bioavailability in rats.
5. Detection of BTK
degradation in Mino cells Mino human mantle cell lymphoma cell line was purchased from ATCC and cultured under the following conditions: in RPM1-1640 + 15% F.BS 1% double antibody, in an incubator at 37 C under 5% CO2. Cells were plated in a 6-well plate, with 5 < 105 cells/well. After plating, the compounds at different concentrations were added and cultured in an incubator at 37 C under 5% CO2 for 48 hours. After culturing, the cells were collected, and RIPA lysis buffer (licyotime, Cat.
P001 3B) was added. The cells were lysed on ice for 15 minutes, and centrifuged at 12000 rpm at 4 C for 10 minutes. The protein sample of the supernatant was collected, and the protein was quantified by using the BCA kit (Beyotime, Cat. P0009), and then the protein was diluted to 0.25 mg/mL. The expressions of BTK (CST, Cat. 8547S) and the internal reference f3-actin (CST, Cat. 3700S) were detected using a fully automated western blot quantitative analyser (Proteinsimple) with a kit (Protein simple, Cat. SM-W004). The expression level of BTK relative to the internal reference was calculated using Compass software, and the DC50 value was calculated using 0rigen9.2 software according to formula (3). Specifically, the BTK
administration denoted the expression level of BTK in administration groups at different doses, and the BTK vehicle denoted the expression level of BTK in the vehicle control group. The results were shown in Table 9.
BTK % = BTK administration/BTK vehicle x 100 formula (3) Table 9 DC50 value of BTK degradation in Mina cells Serial Compound No. DC50 (nM) No.
1 Compound 8-1 22.9 Date Recue/Date Received 2021-09-09 Compound 17 10.9 Conclusion r The compounds synthesized by using the technique of the present invention had a significant degrading effect on BTK in Mino cells.
6. Detection of BTK protein degradation in spleen of mice Female ICR mice, 6-8 weeks old, were purchased from BEIJING VITAL
RIVER LABORATORY ANIMAL TECHNOLOGY CO., LTD, and the experiment was started after 3 days of adaptation. After 3 consecutive days of intragastric administration of different doses of the compound, the spleen of mice was taken, the spleen cells were collected, and RIPA lysis buffer (Beyotime, Cat. P00138) was added. The cells were lysed on ice for 15 minutes, and centrifuged at 12000 rpm at 4 C for 10 minutes. The protein sample of the supernatant was collected, and the protein was quantified by using the BCA kit (Beyotime, Cat. P0009), and then the protein was diluted to 0.25 mg/mL. The expressions of BTK (CST, Cat. 85475) and the internal reference 13-actin (CST, Cat. 3700S) were detected using a fully automated western blot quantitative analyser (Proteinsimple). The expression level of BTK relative to the internal reference was calculated using Compass software, and the DD50 value was calculated using Origen9.2 software according to formula (4).
Specifically, the BTKadmini strat.on denoted the expression level of BTK in administration groups at different doses, and the BTKveh,cle denoted the expression level of BTK in the vehicle control group. The results were shown in Table 10.
BTK% = BTKõdminitiõ/BTK.,,,hick, x 100 formula (4) Table 10 DD50 value of compounds on BTK protein degradation in spleen of mice Serial Compound No. DD50 (nig/kg) No.
1 Compound 8-1 3.8 2 Compound 17 3.8 3 Compound 17-a 19.8 4 Compound 17-b 2.2 5 Compound 18-1 1.9 6 Compound 40 2.1 7 Compound 42 1.9 8 Compound 45 1.4 Date Recue/Date Received 2021-09-09 Conclusion: The compounds synthesized by using the technique of the present invention had a significant degrading effect on BTK protein in spleen of mice.
7. In vitro kinase detection Kinases BTK wt (Cum, Cat. No 08-180) and BIK C481S (Cama, Cat. No 08-547) were prepared into a 2.5x kinase solution, and the substrates FAM-P2 (GL
Biochem, Cat. No. 112394) and ATP ((Sigma, Cat. No. A7699-I G) were prepared into a 2.5x substrate solution, respectively. 5 uL of the compounds at different concentrations were added to a 384-well plate, and 10 p.L of 2.5x kinase solution was added, the cultures were incubated at room temperature for 10 minutes. 10 uL
of 2.5x substrate solution was added, and the mixture was incubated at 28 C for an appropriate period of time. The reaction was stopped by adding 30 viL of stop solution, and the detection was carried out using Caliper EZ reader2 instrument. The IC50 value was calculated using XILFit excel add-in version 5.4Ø8 software. The calculation formula of the inhibition rate was shown in formula (5), wherein max denoted the readout of the DMSO control, min denoted the readout of the negative control, and conversion denoted the readout of the compound Inhibition rate % (max-conversion)/(max-rnin)*100. formula (5) The results were shown in Table 11:
Table 11 1050 value on BTK wt/C481S kinase inhibition Serial No. Compound No. BTK C481S 1050 (nM) BTK wt ICs (nM) 1 Compound 17 8 6.3 Conclusion: The compounds synthesized by using the technique of the present invention had a significant inhibitory effect on BTKwt/C481S kinase.
Date Recue/Date Received 2021-09-09

Claims

Claims 1. A compound represented by general formula (1) or a stereoisorner, a solvate, a prodrug, a metabolite, a pharrnaceutically acceptable salt or a co-crystal thereof, characterized in that B-L-K (I);
L is selected from -Akl -Cyl-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;
Akl, Ak2, Ak3, Ak4 anclAk5 are each independently selected from CH2, 0 or a bond;
Cy 1 Cy2, Cy3 and Cy4 are each independently selected frorn 3- to 12-rnembered heterocyclic ring, 3- to 12-mernbered cycloalkyl, 6- to 10-membered aryl or a bond, wherein the heterocyclic ring, cycloalkyl or aryl is optionally further substituted with 0 to 4 substituents selected from H, F, CI, Br, I, OH, NH2, oxo, CIA
alkyl or C 1-4 alkoxy, and the heterocyclic ring contains 1 to 4 heteroatorns selected frorn 0, S or N;
Cy I , Cy2, Cy3 and Cy4 cannot all be a bond;
when Ak1, Ak2, Ak3, Ak4 or Ak5 is 0, they cannot be directly connected to B;
when Akl, Ak2, Ak3, Ak4 or Ak5 is not a bond, they cannot be directly connected to one another;
when 3 of Cyl , Cy2, Cy3 and Cy4 are a bond, at least one of Akl, Ak2, Ak3, Ak4, and Ak5 is selected frorn CH2 and is connected to B;
when 4 or rnore of Akl, Cyl, Ak2, Cy2, Ak3, Cy3, Ak4, Cy4 and Ak5 are not a bond, at least one of Cyl, Cy2, Cy3 and Cy4 is not piperidyl, piperazinyl, pyrirnidinyl or pyridyl;
B is selected from Bl-W I-B2-B3-B4-;
B1 is selected frorn 6-rnernbered heteroaryl ring or phenyl, wherein the heteroaryl ring or phenyl is optionally further substituted with 0 to 4 R61, and the heteroaryl ring contains 1 to 4 heteroatoms selected from 0, S or N;
WI is selected from -0-, -S-, -NH-, -NHCO- or -CONH-;
Date Recue/Date Received 2021-09-09 B2 is selected from 6-membered heteroaryl ring or phenyl, wherein the heteroaryl ring or phenyl is optionally further substituted with 0 to 4 Rb2, and the heteroaryl ring contains 1 to 4 heteroatoms selected from 0, S or N;
B3 is selected from 8- to 10-membered fused heterocyclic ring, wherein the fused heterocyclic ring is optionally further substituted with 0 to 4 Rb3, and the fused heterocyclic ring contains 1 to 4 heteroatoms selected from 0, S or N;
B4 is selected from 5- to 6-membered saturated heterocyclic ring, wherein the saturated heterocyclic ring is optionally further substituted with 0 to 4 Rb4, and the saturated heterocyclic ring contains 1 to 2 heteroatoms selected frorn 0, S or N;
Rbi, K,-.1.73 or Rm is each independently selected frorn H, F, CI, Br, 1, OH, NH2, CN, CONH2, C14 alkyl or C14 alkoxy, wherein the alkyl and alkoxy are optionally further substituted with 0 to 4 substituents selected from H, F, CI, Br, 1, OH, NH2, CN, CONH2, C1-4 alkyl or C1_4 alkoxy;
(Rm)p, (Rk3),2 Rk5 N
K is selected from O 'Rk4 ;
It' is selected from CF11, C-0, S-0, or S02;
RH, *ski.;
or R" is each independently selected from H, F, Cl, Br, I, OH, NH2, CN, COOH, Ci-.4 alkyl or Ci_4 alkoxy;
)4 12' is selected frorn C=0 or ;
and pl or p2 is each independently selected from 0, 1, 2, 3 or 4.
2.
The compound according to claim 1, or a stereoisorner, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, characterized in that Cyl, Cy2, Cy3 and Cy4 are each independently selected from a bond, 4- to 7-membered mono-heterocyclic ring, 5- to 10-membered fused heterocyclic ring, 6-to 12-membered spiro-heterocyclic ring, 7- to 10-membered bridged-heterocyclic ring, 4- to 7-membered monocycloalkyl, 5- to 10-membered fused cycloalkyl, 6- to 12-membered spiro cycloalkyl, 7- to 10-membered bridged cycloalkyl or 6- to 10-Date Recue/Date Received 2021-09-09 membered aryl, wherein the aryl, cycloalkyl, mono-heterocyclic ring, fused heterocyclic ring, spiro-heterocyclic ring or bridged-heterocyclic ring is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, 1, OH, NH2, oxo, C1_4 alkyl or C1..4 alkoxy, and the mono-heterocyclic ring, fused heterocyclic ring, spiro-heterocyclic ring or bridged-heterocyclic ring contains 1 to 4 heteroatorns selected from 0, S or N;
B1 is selected frorn phenyl or pyridyl, wherein the phenyl or pyridyl is optionally further substituted with 0 to 4 lei, and the heteroaryl ring contains 1 to 4 heteroatoms selected from 0, S or N;
W1 is selected from -0-, -NHCO- or -CONH-;
B2 is selected from phenyl or pyridyl, wherein the phenyl or pyridyl is optionally further substituted with 0 to 4 111'2, and the heteroaryl ring contains 1 to 4 heteroatorns selected from 0, S or N;
B3 is selected from substituted or unsubstitutal irnidazopyrimidine, pyrazolopyrirnidine, irnidazopyrazine, pyrazolopyrazine, irnidazotetrahydropyrirnidine, or pyrazolotetrahydropyrimidine which, when substituted, is optionally further substituted with 0 to 4 Rh3, and the fused heterocyclic ring contains 1 to 4 heteroatoms selected from 0, S or N; and B4 is selected from substituted or unsubstituted azacyclopentyl, piperidine or piperazine, wherein the azacyclopentyl, piperi dine or piperazine is optionally further substituted with 0 to 4 le4, and the saturated heterocyclic ring contains 1 to heteroatorns selected from 0, S or N.
3.
The compound according to claim 2, or a stercoisorner, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, characterized in that Cy 1 , Cy2, Cy3 and Cy4 are each independently selected from one of the following substituted or unsubstituted groups: a bond, phenyl, naphthyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutyl-fused-cyclobutyl, cyclobutyl-fused-cyclopentyl, cyclobutyl-fused-cyclohexyl, cyclopentyl-fused-cyclopentyl, cyclopentyl-fused-cyclohcxyl, cyc lohexyl-fused-cyclohexyl, cyclopropyl-fused-cyclobutyl, Date Recue/Date Received 2021-09-09 60-60-1=ZOZ panpoal 3pcu3ri3a ele0 `1App0c10-04s-pC)coq0piCaezu 'IAPIJ0dId -oi tdslicW0d0 oicarzr 'pcmlad!d-oilds-pcu!ppozr lAppad!d-oilds-p(xpqo pi(D
'Ircm_mclilci-oi!ds-jkluodopXo 'licppocl!d-aqds-IX1nciopXo [XxNopicarze-cuids -pcx-otioloicanzr. `1c1uodolo/N3z-e-cu!ds-pcxotiopic:w7B lictilppozr-o4s-IXxotiopicarzu .. sz µpcxoliopi(Duz-e-wlds-pCluodoTaiCmzu lAluodopiCpuzu-oildsliCluadopiCarze `pcupiazu-oi!ds-liCluodop/Cpuzu `pCxoqopiCauzu-o4s-I1CwIlozu '1/Cluodop/Couzu -oi!cisliCump.-.1711 /Culp!
pz-n-01 Ids-IrCunwr 'licxorioini[nrzp-oiids-1X3catio13,6 'pcluadopicarze-ol!ds-TXxotrioXa licumpoze-oi!ds-pcxotiopX3 '1Xxot1opiarzu lic2uOdoloic3uzu-cu!cts-ticluodoloico `Ticuppze-ol!dslicluodoloico oz `IXxoqojoiCauz-e-oildsliCinqop/CD 'ikluodoptCorzu-oilds-IAIncpopiCo liCulppozu-culds -pCmciojoiCo `I/CppocIld-posnj-pCxotiojoiCpuzu '1XxogoioXpuzu-pasnj-pCxogoioXpuzu `iicp.mtiopiCouzu-psnj-iiCxagoio/C3uzu liCulppozE-posnj-pcx01401/carzu snj- i/ClwdoloAoezt `ticxottojnicaezr-posnjlicluodoin our 'licluodo[oicarze-posnj-pcluodoioXauzu '1Xu!pp,ozu-posnj-iXiuodoloXanzu .. ST
`pCppoci!ci-posnj-pCuIppozu '1XxotiopiCoeze-posnj-pCulpIpzu `I/CluodolaXpezu-posnj lAulppoze `pCuIppozu-posnj-IrCulppozu 1/CppodIckposnj-j/CxotiopiCo '1AxotiopiCo-uzu -psnj-pCxoqopXo 'I/CluodopiCauTe-psnj-pCxoqopiCo IiCti!mozu-posnj-pCxpqopiCo Ii(ppod!d-posnj-EXTuodoloico '1Xxoqop/iorze-posnj-j/cluodoloXo `iicluodoioXorzu -posnj-pcluodolarco 'ircuippoze-posnj-ircluodoloico licppod!ct-posnj-pcmcio jo o OT
`pcxorpiatcauzu-rosnj-pcmciojaico 'pcluo,dopicopzu-posnytcinctopi{a lImpzu -posnj-jAmqop/Co liCppodId-posnj-pCdcadopiCo liCxatiopiCaezt-posnj-pCdoidop/Co `jkluodopiCouzu-posrg-pCdoJdopiCo liCumpozu-posnj-ptdoidopiCa `pCjozanol `I/Cjozmil 41XtiyaiXd 'EXulmuipXd liCu171pp-Xd 'I NJ ci 41.K[ozr!til '1XioTep!ttil licuvaiod!d `pcuuottatow '14.!.tod!d IXittodopicotz.e '1Xu!pport `pcxoqopico -oi!cislÅcloidopÅo `IXwociojoico-oilds-pcdoldoloito '1Xvictopico-ands-pcdoldoloico 4pCxogoloiCo-oi!ds-i,NoilopXo 'IiCxotiopiCo-oilds-pCluodopiCo `pCiuodoloiCo-onds `pCxotiojoiCo-oilds-pCmciapiC.D '1X4uodoio/CD-oi!ds-pCmclopICD `pCmciopiCo 'pfxogolo/Co-posnj-pCdoadopiCo `pCluodopiCo-posnitCdoldopiCo 0 , which, when substituted, are optionally further substituted with 0 to 4 substituents selected from H, F, CI, Br, I, OH, NH2, oxo, C1-4 alkyl or CIA alkoxy;
N {Rt'3),,7 --."--,!(W3)"5 HN
\
(Rnro (Rb2k N (Rb26}(N
(hi \-4iNt N
---B is selected from (Rb4),, or o N A
NNH' (Rb')o =
Rb Rb2 Rb3or Rb4 is each independently selected from H, F, CI, Br, I, OH, NH2, CN, CONH2, methyl or methoxy, wherein the methyl or methoxy is optionally further substituted with 0 to 4 substituents selected from H, F, CI, Br or 1;
n I, n2, n3, n4, n5, n6, n7, n8, n9, n10, n11, and n12 are each independently to selected from 0, I , 2, 3 or 4;
(Rk3).p2 (.
R" =\
(Rkt)pi ).p2 N
K is selected from o o sFe4 or O 1R.1,4 ;
Rk2 is selected frorn CH2 or C=0;
Rki, Rk3 or K. is each independently selected from H, F, CI, Br, I, OH or NH2;
and 15 p I or p2 is each independently selected from 0, I or 2.
4.
The cornpound according to claim 3, or a stereoisorner, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, characterized in that Date Recue/Date Received 2021-09-09 X ______________________________________________ N\
L is selected from - -I
1-( ____________________________ \ \ ., N--( N-s:
/ /
/
¨N \---------/ 1 , , _N
\ /
\N 5 5 + c ,i_N _____________________________ KNI- j:\v ( \N¨CNI-)----N \NI-- \
1-( N CN1-\ õ "
Ni- -1--\",N-- \N \N¨N--1-_________________ / /
-1-( \N-I- -t-CN¨( \N¨( \N¨( '\NI-N N p----C

ff-NyNCiNk j=CN-=-- N 0 --\N¨CN-1-\ ---/ 1-CN-C)--C;
or L can be selected frorn ' , , F
F F
-1,_-\ F
trans) (cib) ', N,r---N N-....r.--N

\ \ \
ii=- 7N¨CN-1- ' i= = ( ____ 71-CN-1- 1 = /N¨CN-1- N __ -CN-i--1---OCN ........................ -CN-i 1 CN -- =CN ________ -CN--4- \
-1.--N--( or _______________________________________________ N4--, , Date Recue/Date Received 2021-09-09 -µ-( \N-0-- - 1 1-0CN-OCNI-or L can be selected from H H H
1¨CIN¨OCN-i- 1-CN-CiN
-K:CN¨OCN-E
I-CON-CON+ --N N Ni- 1- ¨OCN1-, H
1 N-OCN-V 1 N ___________ 01+ 1-C---N---N-1-H
H
-N--CNI- A...CN ________ CN __ CN.1_ or -i¨CN¨CON-1-L is connected to B on the left side, and is connected to K on the right side;
N-.:. N'-',N p --,_ 112N---L1.4.
N N
N / FiN"'y N
N
-C- ) a 0 B is selected from FiN1 HAI / \>

a N /

õ , N--"\---01 N
N-,..\

\ / N
r Z¨c__/
N
or B can be selected from '' 7 N:-_-_-H2N \ , t51,-,-, N-,, \ N
/ H2N¨ 1 H2N¨ , 1 \ / N \ / N
F F F
0 \ N
N- 0 = -N
N 0 \ N
{trans) (cs) Date Recue/Date Received 2021-09-09 N-_-_-, H2N H2N ,N-..,--.\
, - 1 \ N 1 \ N
/ F ---,,,N F / F
-- --0- \ / \N-N,,,,, 0 = \4h----1 N-N) C-5 -...,...õ..N.s.. a ,N,.., a =,...õ.õNs_ 01, 9 0-0 ,r-N4N
N ---.
o \ / 0 )-H2N N..0 H2N \ t4' CNµ--.--or ; K is selected from H
o 0 ()--N0 s , __ --,...
' N-2) -1-1----7N
._../-0 '&..
H NH FL
O 0 0 0 Or ."----- 'N- -"' =
, , V
\ / ___________________________________ o or K can be selected frorn F .

5. The compound according to claim 4, or a stercoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, characterized in that o N-c._ (1) N----c -\C) 'N. NH
K is selected from 0 0 , 0 0 , o 0 0 0 o o EI -1,(N 0 0 NH I( NH
N

N.- 0 F F F ,N¨\)\-- ,/,=0 _:2,t Nu-4¨NH F
N Z--NH F NH
(-) tO N 0 A A A

, , , Date Recue/Date Received 2021-09-09 =Cji N¨c-NH 0 --\=KN-----NH 100 --e 0 ¨c NH
"1¨ 0 0 0 0 0 0 0 0 , ' H

0 ".-"" "--7" 0 N 0 H H
0 N 0 0 0,.Nya N -"Ai Çx N N
N - 4111112-P N -- or .
, 6. The cornpound according to claitn 4, or a stereoisorner, a solvate, a prodrug, a rnetabolite, a pharrnaceutically acceptable salt or a co-crystal thereof, characterized in that o o o N.\--7 \ N4).7¨NH F
K is selected from o 0 0 0 ' 0 ' t o o .....tN; F NFI
,k ---M-1 N 0 Nio- 0 0 ,zzz.

, , , H
0 0 0,_.N,0 F ....¨NFI -4' 0 ---.- ------N =C) N"-------=
CI
0 0 0 or N
, .
7. The compound according to claim 4, or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, characterized in that B is selected frorn N,=N

._. N¨CN1-N
a a =
, Date Recue/Date Received 2021-09-09 N H2NN-_,) , 0 \N-Nb s) a tran I-or B can be selected from 6 , , N,---, N_,--, H2N 1_14N
N._.--_-\
H2N - \ H2N - \
F ' F
a N
N_,, F H,N -IN,µN
\ /N
0 = -Nõõ,...õ-1..,1 0 ----0-4N-N/,, j) b N
.....õN", or 8. The compound according to claim 4, or a stercoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, characterized in that B is selected frorn H2N N. A
--NN-C--.-I) , ,N

....01 I
or B can be selected from N-. N .
9.
The cornpound according to claim 4, or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, characterized in that is B is selected from Date Recue/Date Received 2021-09-09 NH2 Eod N

=

1.
r,j4 HN
or B can be selected from O. The cornpound according to claim 4, or a stereoisorner, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, characterized in that B is selected frorn r NH
`c) NH
or B can be selected from 11. The cornpound according to clairn 2, or a stereoisorner, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, characterized in that the compound is selected from a compound represented by general forrnula (la) or (lb), B-Cy1-Cy2-1( (Ta) B-Cyl-Cy2-Cy3-K (Tb) Date Recue/Date Received 2021-09-09 N,---'NN N------',N
I/2N N. i H2NFì
-N ______________ -N __ n --- 0 ' B is selected from L\---2---0 ' 1 Q
, H2N- N-_,...\
N /
,C5 , Nz, _-- F ¨
{trans) = --...õ....õ-N,A ill -....,,NtA a ...,...1\1õ, , N a "------- Nte....
-...N,õ
P is 0 0õ
, (----N---,õ
\ , ft-- ¨

¨N
14 H4N>\ -- --11 or N Nil > C-V )¨
_ --r--- 1 .N3 NH
o ;
Cyl, Cy2, and Cy3 are each independently selected from one of the following substituted or unsubstituted groups: 4- to 6-membered nitrogen-containing mono-heterocyclic ring, 5- to 10-membered nitrogen-containing fused heterocyclic ring, 6-to 10-membered nitrogen-containing spiro-heterocyclic ring, 4- to 6-rnembered monocycloalkyl or phenyl, wherein the phenyl, cycloalkyl, rnono-heterocyclic ring, fused heterocyclic ring or spiro-heterocyclic ring is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH,, oxo, CI 4 alkyl or alkoxy, and the mono-heterocyclic ring, fused heterocyclic ring or spiro-heterocyclic ring contains 1 to 4 heteroatoms selected from 0, S or N; and Date Recue/Date Received 2021-09-09 00,N, _.-0 ."--- -----_ __________________________ K is selected from , 0 h or F 0 .
12. The compound according to claim 11, or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, characterized in that Cyl, Cy2, and Cy3 are each independently selected from one of the following b ___________________________________________________ N
( __ \N- i ¨N1- , s 7---------\ , µ -N N-r substituted or unsubstituted groups: \--------/
, , p-1- )c_ --CNi- o ,,.. Nil 0 Nt -F01- 1-N( F F
N _________ KN+
F F F F
_ , _,..,...õ.
c tran ' cis ---,...,..N 4 N4 N?.. N4 _FCCN1_ F
/-------L'i or c' ; and o i 0 \ r--, ---- N
"---z, N o 0 K is selected from o o 0 0 , o o o o o o -k NH
kNi=\.¨NF-1_(:) NH
¨t N õ.,,C.) F F F.----0 o 0 Date Recue/Date Received 2021-09-09 .....Z\--NH F NH
N 0 Nu- 0 N 0 , , , N^ ¨c 0 -1cr'j¨c 0 N

NH NH
i 0 o 0 0 0 0 o 0 , ' ' H

H H
N 0 0 ,N 0 0 , 0 N
N - NI/ `-... C01.--N
e...-c N i N....õ-1.õ, ...-- e.-1-___ - -N or N
.
13. A compound or a stereoisomer, a solvate, a prodrug, a metabolite, a phannaceutically acceptable salt or a co-crystal thereof, characterized in that the compound is of the structure selected from one of:
o 0 o o Q
0 N--,--=N
, N ,,__ ___,, N'crj1-1 N-CN-C ---14\ j..,:N . 0 0. 0 0 N, ___CN-CIN
."' ---14 -N
-....., ..._...._4- N I
..._ N.---/
to 0 r------/---c) 0 1-------e N.-----N
NH
H2N N. -14, H2N N ' Ni=-=Fr __ .N-CN-Cri-NCN
N 0 N-CN-C, N/).-NDC 0 ' N --,.,.-).---0 H2N _N 0 / H2N N, 0 *
0 ,N

\

N.--N___\-,0 N_0,, 0 .

N.----'\N H2N _N
0 -,---:-., Fl2N \ A

--N
N
-- , ---C\N
o N-N t i-NH

\----cN---CN
N,Thr NH
o Date Recue/Date Received 2021-09-09 (1.3 _,,...õ
1..., -^N-C

0 ,0 0 0._,,,, .../,µõ---No*, o , p ---õ, * tt _CIIIN
()---.,,CN0, o *
N
N---H2N N 42N-r4N
Nr----/ N
% 0 N='' 1 ),,,N.,_ \_,,r'N---C-iN
j........y --- N

QH N ihi4--N

P = / N
o c N,r_ N, - N-C\N-04- -N= * 0 0 *
N. _CN-\='---N
,N 0 N-=- \>=0 H2N-eN
N
N-----,/ 0 o 0 9 = N71 t _/0 N

N W---/

P
Fll..4 QNN
_CN-CN 0 i õ.
."-= N ! I
H2N' N
Date Recue/Date Received 2021-09-09 N-r-N
0 H2N \ õfrq - F
0 / \ N, N j (cis) N'-\N
N=l kiN

,c Fõ,,.(R) F

'-' '1,4 0 0 iii - N, 0 H2N ._.}-N / K
H2N) \ N
N=I N=-/
Q

,,--N - Nt4..,-"i_ c 4.=,(R) _CiN --- N

0 / \ N

N 1. il j'N--Cir / \ N H2N
N-=-/ H2N--VN
N--/
N'- N, -%
H2,,,, , . \ / N H2N\ / N
F

C5 i'L'Itrars) N__, 1 z N-,-..
H2N -1 H.2N-p \ / N
F
0 'Iv N.y.--1,1 c5 ' , NJ-A

\ ,N H2NI.,N
F
. NN'N---C\ 0 0 H
iii N-r,4 ...---0 p H

N, __GN-Crli 0 N 0 \
/ \N 'IµlH ---N 'N--X N-- N-C \IN --c, 0 /
H2N H2N 7 µ
N=7 0 ni,--._-,- ,N
Date Recue/Date Received 2021-09-09 U z , 0 0 H 0 = Z C5 Nic H2N / \ N N

9 c? . 0 ,D
N----ti --- -"" N ---, N
H2N- / \ NN ,.) NH H2N / \ N
N 0 N..=-/
N,--/ 0 40 0 0 o . 0 if? 0 \>\.-NH 'Lc NH
___________________________________ 0 H2N -N f"-- N---CJIN 0 H2N - Nii õCy "-C----- Al --'N'----j /
N-N - rH
b .--1-1 )--N -N
N---.CN
i ______________________________________________ CN

1 ' ...-" H

0,,....z.õNõ,õ.õ0 0 1.--- ----- -N
H2N \ NNiN
N
N"------- \
HNµj..,,.( W..' \
1 H2N \ N
----.0 o H
/N.õ,,C, N--õ--"\
.\,,N 0 =.--.N
'==.0 o y ,e-H2N ) , -.--N
F
\

Date Recue/Date Received 2021-09-09 CL p 0 , 0 r---N--c 0---,1 N
0 0 N'''EIN,IIH
....,, -0 NH2 N) %
NH
N

Ni 0 0 0 i_i ' - /

-N N
___N = 0 NI- $ \ / (tarts) 0 N
\CliZI,H

.---- I '''CiN N..01 0 N .... N
N N
0 /-.=N
___,.., _0......, ...õ
= 1 N a ) r 0 N 0 H2N / \ N
Nt.i,H 0 = 0 O \

N/)--N _CN _ON --- 'NI 0 N

H2N.--4N
N'=,/
-.fNH

Q r---\
N/

f\----- N 0 H.,2N
O N
--- / . N 0 0 N

H
N----ri \JH

co IS
T

F
=--. / --, (13) 0 F
.....n - , 0 Date Recue/Date Received 2021-09-09 ici) .---F F
(R) 0 N N*
H2N - / NH H2N- / \

Q / N

F N._?:-.7LI
_ q' -0 F,,,, IRI,,,, 1-'1'4--,N1 --- -' N
H7N / \ N
/ \ N H2N N=4 N"--=-/
0 0 C) 0 NH NH
N ---- N
, _../o -- -" -N' H2N / \ N H2N / \ N
N=-,' ..c.72 F NH
._ON--./

--- ,..--t , Oral 0 / \ N (l_ J-NN 0 C5 N --ndo 1 --- -' -N
/ \ H2N N C\N je _OZ--NH
N----/
i...)...? ==0 9 F C) 0 --- -" NN(;., / \ N
N 0 H2N N2N \ N ON--CJN--CN--- .. 0 N-=''' HN H

Q , . _ _ . t N/ ,, =
7--- N -- N __C/N
..tiCiN-- i 0 Nr _r-N 0 0 o / \ N, N
N PINI--__ "" N- `=,---/ 0 i ________________________________________________ ( Q H2N ' \ N hi N-=/ N--=-/ 0 0 0 0 , = / -\ NH
0 / \ N N-4.-Y 0 NN ---/r4 ''' _---I
( H2N / \ N H2N / \ N
N=-1 .-.2 Date Recue/Date Received 2021-09-09 (3 . , \N-N --(--1 F 0 \NI 3 \ 1.--n F

NH
N.,...r.õ1 t,..,N;

0._ NI if H 0 0___,,, 00._.__ .)-----/' N -N

---'N 0 H2 HN "
\ 1 H2N N N ¨
3''CN
HN
H
O. , N. .0 FW,,,, 1-1,N A \
disek----1 N .4---- 0 a .1._ ci ,C) H H
r 0 cY,:r CI) 0 Fr".1 H 0 I ---OCN 1µ * 1 H H,N N
Nr---- \ rµi H2N- \ IN
H2N \ q ..... .... N
_ N

* \ /
---..

0 .--- ---e."
N-:-----N P
H2N 0 --- N____/N1 /NI _r, vv=s¨Ciq N=/

=
Date Recue/Date Received 2021-09-09 N

N2N \ N N=i rv=/
o 0 111 _oCIN I

N t4-04 ,N,w0 H2N \ N
o /-12N NThrm-, 4:0 /
=

14. The compound according to any one of claims 1 to 13, or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, characterized in that the salt is selected from trifluoroacetate.
1 5. A pharmaceutical composition, comprising the compound according to any one of claims 1 to 14, or a stereoisomer, a solvate, a proclrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, and a pharmaceutically acceptable carrier.
16. Use of the compound according to any one of claims 1 to 14, or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof in the manufacture of a medicament for treating diseases related to BTK activity or expression level.
17. Use of the compound according to any one of claims 1 to 14, or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or Date Recue/Date Received 2021-09-09 a co-crystal thereof in the manufacture of a medicament for treating diseases related to the inhibition or degradation of BTK.
18. Use according to any one of clairns 16-17, characterized in that the disease is selected from tumors or autoimrnune diseases.
19. Use according to clairn 18, characterized in that the tumor is selected from non-l-lodgkin's lymphoma, chronic lymphocytic leukaemia, mantle cell lymphoma, or 13 cell lyrnphorna; and the autoimmune disease is selected from rheumatoid arthritis or psoriasis.
Date Recue/Date Received 2021-09-09